Stereospecific hydrogenation of benzopyrans



United States Patent 3,544,598 STEREOSPECIFIC HYDROGENATION 0F BENZOPYRANS Gabriel Saucy, Essex Fells, N.J., assignor to Holimann- La Roche Inc., Nutley, N.J., a corporation of Ne Jersey No Drawing. Continuation-impart of application Ser. No.

633,730, Apr. 28, 1967, which is a continuation-inpart of application Ser. No. 604,124, Dec. 23, 1966, which in turn is a continuation-in-part of application Ser. No. 549,816, May 13, 1966. This application Nov. 2, 1967, Ser. No. 679,989

Int. Cl. C07d 15/04 US. Cl. 260-3403 10 Claims ABSTRACT OF THE DISCLOSURE Stereo-specific total synthesis of steroidal materials. 7- substituted 3-oXo-1-heptenes or variants thereof are reacted with 2-alkylcycloalkane-1,3-diones yielding 3-substituted 6aB-alkylcyclopenta[f][1]benzopyrans or naphtho[2,1-b]pyrans. These are then subjected to a selective catalytic hydrogenation followed by an introduction of a hydroxy, alkoxy or acyloxy group at the la-position to produce a 3-substituted 6ap,4a-hydroxy, alkoxy or acyloxy perhydrocyclopenta[f][1]benzopyran or perhydronaphtho-[2,1-b]pyran. These latter compounds are then converted into 4-or 5-(3-oxoalkyl)perhydroindene-S-ones or perhydronaphthalene-6-ones which inturn can be converted to known steoidal materials by known methods.

RELATED APPLICATIONS This application is a continuation-in-part of applicants copending application Ser. No. 633,730, filed Apr. 26, 1967, which was filed as a continuation-in-part of applicants copending application Ser. No. 604,124, filed Dec. 23, 1966, now abandoned, which was filed as a continuation-in-part of applicants copending application Ser. No. 549,816, filed May 13, 1966, now abandoned.

BACKGROUND OF THE INVENTION Cyclopenta [f] 1]-benzopyrans and 7H-naphtho [2,1- b] pyrans are valuable as intermediates in the total synthesis of steroids. Total synthesis utilizing these compounds as intermediates are described in US. patent applications of Gabriel Saucy: Ser. No. 549,816, filed Dec. 23, 1966 now abandoned; Ser. No. 604,124 filed May 13, 1966; Ser. No. 633,730, filed Apr. 26, 1967, now abandoned. Other related applications include Ser. No. 633,693, filed Apr.

26, 1967, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION This invention is concerned with certain polycyclic compounds and with processes for their synthesis. More particularly, this invention relates to novel cyclopenta[f] [1]-benzopyrans and 7H-naphtho[2, 1-b]pyrans, and to methods for their production. These compounds are useful as intermediates in synthesis of steroids and D-homosteroids, respectively. In syntheses of steroidal materials steric considerations are of great significance. The most used steroidal compounds are those having a C/D-trans ring junction with the substituent in the 13-position being in the fl-stereoconfiguration. The present invention provides a facile total synthesis of 13B-C/D-trans-steroidal Patented Dec. 1, 1970 materials. This desirable result is obtained via a unique asymmertic induction with optical specificity preserved in subsequent reaction steps.

In a major aspect, this invention is concerned with novel cyclopenta [f] [1]benzopyrans having the tricyclic nucleus and novel naphtho[2,l-b]pyrans having the tricyclic nucleus.

6 7 5 s Q 10 0 4 V a 2 These novel compounds are generally defined by the formula:

wherein Y is a 3-oxobuty1 [R CH COCH(R )CH(R or R; R is hydrogen, an alkyl group of from 1 to 6 carbons, or a 3-substituted butyl radical of the formula R5CH2C(R3,R4)CH(R14CH(R15)-; R1 is a primary group of from 1 to 5 carbon atoms; R is hydrogen, lower primary alkyl, or lower acyl; R when taken alone, is OR R when taken alone, is hydrogen; R and R when taken together, are lower alkylenedioxy, the monothia, monoaza or dithia chalcogen thereof; R R R R and R are each independently hydrogen or lower alkyl; R is hydrogen, lower alkyl, lower acyl or lower oxyhydrocarbyl; Z is carbonyl or a group of the formula R is hydrogen of lower acryl; R is hydrogen or lower aliphatic hydrocarbyl; T represents either a single or a double bond; U represents a single or a double bond and is a single bond when T is a single bond; m is an integer having a value of from 1 to 2; n is an integer having a value of [from to l and -is 0 when T represents a double bond and is 1 when T represents a single bond; r is an integer having a value of from 0 to 1 and is 0 when T is a double bond and 1 when T is a single bond; and sis an integer having a value of from 0 to 1 and is 0 when U is a double bond and 1 when U is a single bond.

As used throughout the specification and appended claims, the term hydrocarbyl group denotes a monovalent substituent consisting solely of carbon and hydrogen; the term hydrocarbylene denotes a divalent substituent consisting solely of carbon and hydrogen and having its valence bonds from different carbons; the term aliphatic, with reference to hydrocarbyl or hydrocarbylene groups, denotes groups containing no aromatic unsaturation, but which can be otherwise saturated or unsaturated, i.e., an alkyl or alkylene, or an aliphatic group containing olefinic or acetylenic unsaturation; the term alkyl group denotes a saturated hydrocarbyl group, whether straight or branched chain; the term primary alkyl group denotes an alkyl group having its valence bond from a carbon bonded to at least two hydrogens; the term acyl group denotes a group consisting of the residue of a hydrocarbyl monocarboxylic acid formed by removal of the hydroxyl portion of the carboxyl group; the term oxyhydrocarbyl denotes a monovalent saturated cyclic or acyclic group group consisting of carbon, hydrogen, and oxygen containing only one oxygen in the form of an ether linkage; and the term lower, as applied to any of the foregoing groups, denotes a group having a carbon skeleton containing up to and including eight carbons, such as methyl, ethyl, butyl, tert.-butyl, hexyl, Z-ethylhexyl, vinyl, butenyl, hexenyl, ethinyl, ethylene, methylene, formyl, acetyl, 2-phenylethyl, benzoyl, methoxymethyl, l-methoxyethyl, tetrahydropyran-Z-yl, and the like. The phraseology lower alkylenedioxy, the monothia, monoaza or dithia chalcogen thereof is used to indicate a ketalized oxo or thio moiety and comprehends' moieties of the formula OR O, OR S-, OR N- or SR S wherein R is lower alkylene. Exemplary moieties are 1,2-ethylenedioxy, 2,2-dimethyll,-propylenedioxy, 1,2-ethylenedimercapto, 2,3-butylenedioxy and the like.

In the formulas presented herein, the various substituents on cyclic compounds are joined to the cyclic nucleus by one of three notations, a solid line indicating a substituent which is in the S-orientation (i.e., above the plane of the paper), a dotted line indicating a substituent which is in the rat-orientation (below the plane of the paper), or a wavy line indicating a substituent which may be in either the aor ,B-orientation. The position of R, has been arbitrarily indicated as the fl-orientation, although the products obtained in the examples are all racemic compounds unless otherwise specified.

Preferred compounds are those wherein Y is R; R is nalkyl, especially methyl, 3,3-(alkylenedioxy)butyl wherein the alkylenedioxy group, when taken with the 3-carbon of the butyl radical, forms a dioxolane ring system, especially 3,3-(ethylenedioxy)butyl and 3,3-(2',3'-butylenedioxy)-butyl; 3-hydroxybutyl, 3 tert. alkoxbutyl, especially 3-tert.-butoxybutyl, or 3-(tetrahydropyran-2- yloxy)butyl; R is n-alkyl, especially methyl and ethyl; and, when s has a value of 1, the 9a- (when m is 1) or 1011- (when m is 2) hydrogen is trans-oriented with respect to R Subgeneric to the tricyclic compounds of Formula I are the 3-substituted 6a}? alkyl 1,2,3,5,6,6a,7,8-octahydrocyclopenta[f] [l]benzopyrans (by alternate nomenclature 3-substituted-6afl-alkyl-2,3,5,6,6a,8-hexahydro-1H- cyclopenta[f] [1]-benzopyrans) and the 3-substituted-6a13- alkyl 1,2,5,6,6a,7,8,9 octahydro-3H-naphtho[2,1-b]- pyrans (by alternate nomenclature 3-substituted 6aflalkyl 1,2,3,5,6,6a,8,9 octahydro-7H-naphtho[2,1-b]- 4 pyrans), hereinafter referred to as dienes, having the formula:

O YCHZ k/ H wherein R R R Z, Y, and m are as defined above;

( ZLn wherein R R R Z, Y, and m are as defined above;

and the 3-substituted-6afi-alky1-4a-hydroxyperhydrocyclopenta[f][1]benzopyrans and the 3-substituted-6afl-alkyl- 4a-hydroxyperhydro-3H-naphtho[2,l-b]pyrans and their lower alkyl ethers and monoacyl esters, hereinafter referred to as perhydro compounds, represented by the formula:

YCHZNVV R11 R12 (Ic) wherein R R R R Z, Y, and mare as defined above.

Alternatively, the tricyclic compounds of Formula I can be classified according to the nature of Y, which determines the utility of the compounds of this invention. The first of these classes are the 3-alkyl compounds of the formula:

wherein R R R R Z, m, n, r, s, T, and U are as defined above and x is an integer having a value of from 0 to 6, inclusive.

These products are useful as intermediates for the synthesis of members of a recently discovered class of 913,10-

or retrosteroids, and also are useful as intermediates for the synthesis of 10a-steroids, and other steroidal materials.

The second class of intermediates classified according to utility are the 3-(4-substituted pentyl) compounds of the formula:

T ,,J 1 o H.

R12 (It) whe-rein R1, R2 R R11 R12, R14, R15 21 T,

and U are as defined above; A is carbonyl or CR R and R and R are as defined above.

These compounds, which are useful as intermediates for the synthesis of 19-n0r-steroids of the normal series, and other steroidal materials, can be further classified as:

(1) The 3-(4-oxopentyl)substituted cyclopentabenzopyrans and naphthopyrans of the formula:

1120 Hr (CHM morn error-mm cyclopentabenzopyrans and naphthopyrans and side chain chalcogens of the formula:

wherein 1 2, 5 9, 11 12 14 15, T, and U are as defined above; and both h are either sulfur or oxygen, or one h is oxygen and the other is sulfur or nitrogen, and

(3) The 3-(4 hydroxypetyl)-substituted cyclopentabenzopyrans and naphthopyrans and ethers thereof of the formula:

wherein 1 2 5 6, 11 12, 14, 15, "r

T, and U are as defined above.

In compounds of Formula Ie-4, R as t-butyl is especially preferred.

In a second aspect, this invention is concerned with a method for producing the compounds of Formula I via the following general reaction scheme:

l (III) Li ks).

l 12 (lb) wherein Y, R R R R Z, and m are as defined above; and B is hydrogen, lower alkyl or lower acyl.

Thus, the process of this invention comprises the general steps of (1) condensation of a 7-hydroxy-1-alken-3- one or a variant thereof (II), as defined below, with a 2- alkylcycloalkane-1,3-dione (III), as defined below, to produce diene (Ia); (2) saturation of the 9,9aor 10,100- double bond of diene (Ia) to produce monoene (Ib); and (3) introduction of a hydroxy, alkoxy, or acyloxy group at the 4a-position and a hydrogen atom at the 9bor IOb-position of monoene (1b) to produce perhydro compound (Ic). It is to be understood that the foregoing reaction sequence is merely schematic in nature, and that each depicted step can represent only one or more than one reaction, as will be more fully described herein.

It will be noted that the diene, monoene and perhydro compounds of this invention can bear a 3-(4-oxopentyl)- substituent. When such a side chain is desired, it is however preferable to perform the reaction sequence with compounds having the 0x0 moiety of the 4-oxopentyl side chain in protected form. Protection can be effected by ketalization (to form lower alkylenedioxy, the monothia, monoaza or dithia chalcogen thereof), or by reduction to a hydroxy moiety optionally followed by etherification or esterification. The oxo moiety can be regenerated at any intermediate stage as desired.

l-alken-3-one compounds of Formula II are employed as one of the starting materials for the foregoing reaction sequence. Illustrative examples of these 1-alken-3-ones includes 7-hydroxy-l-octen-3-one, 7-hydroxy-1-nonene-3- one, 7-hydroxy-1-dodecen-3-one, 7-acetoxy-1-nonen-3- one, 7-benzoyloxy-1-n0nen-3-one, 7-methoxy-l-nonen-3- one, 7-benzyloxy-1-nonen-3-one, 11,11-ethylenedioxy-7- hydroxy 1 dodecen-3-one, 7,11-dihydroxy-1-dodecen-3- one, 11-tert.-butoxy-7-hydroxy-1-dodecen-3-one, ll-(tettrahydropyran 2-yloxy)-7-hydroxy-1-dodecen-3-one, and the like.

The 7-hydroxya1ken-3-ones of Formula II above are readily synthesized from (A) a glutaric acid anhydride, (B) a 2-alkylcyclohexane-1,3-dione, (C) a glutaraldehyde or (D) a butyrolactone, as is illustrated by the following sequences leading to 7-hydroxynonen-l-ones:

O O I ll n O-- Ru i i R12 R12 0 lg H HO CH(" HCHCOa1ky1 Ru 1 Cl CHCIJHCHzJJ O-a1ky1' O I ll 0 RCHzCCHCHCHgHlO-BIIWI v Rom MR R12 2 The preparation of starting materials useful in the practice of the present invention is described in greater detail in US. patent application of David A. Andrews and Gabriel Saucy, Ser. No. 633,693, filed April 26, 1967, entitled, 6-Substituted Tetrahydropyran-Z-ols and Process for Their Preparation; and in US. patent application Ser. No. 604,124, filed Dec. 23, 1966, now abandoned entitled a-Olefins.

The dienes of Formula la in the presence of water and 10 acid, e.g., sulfuric acid in acetone, aqueous acetic acid or O- Rn AWRW 0 5 Cl CHC'HCH2C1 1 RCHzCHCfHCHzCl ?H o I? P YCH2CCHCHCHzCHCH=CH2 YOHz Rn lIVa OH (|)H YCHzJJHOHSJHCHzOHCH=CHz I ll YCHzCHCHCHCHzC CH=CH2 aqueous hydrochloric acid in dioxane, undergo acid bydrolysis to form indenones of the formula wherein R R R Y and m have the same meaning as above.

The indenones of Formula Ia are themselves convertible to compounds of Formula Ia via dehydration, for example, via acid catalyzed azeotropic distillation in ben zene. Suitable acid catalysts are p-toluenesulfonic acid, potassium bisulfate, boron trifluoride etherate and the like. This reversible hydrolysis of compounds of Formula la is useful in their preparation and purification. Thus, in instances where the direct purification of compounds of Formula Ia is difficult it is often more facile to hydrolyze the compound of Formula Ia to a compound of Formula Ia, which can then be purified, for example, by chromatography, and subsequently be reconvertcd to the desired compound of Formula Ia via dehydration.

The ketodienes of Formula Ia-l are readily converted to the corresponding 7j3-a1cohols and their esters as represented by the formula:

R1 r I l YCHW k/ Rn wherein Y, R R R R and m are as previously defined,

employed herein, is meant a Group I-metal having an atomic number of from 3 to 19, inclusive, i.e. lithium, sodium, and potassium. Group III-metals include those having atomic numbers of from 5 to 13, inclusive, i.e., boron and aluminum. Illustrative examples of these re ducing agents include an alkali metal, preferably lithium or sodium, in liquid ammonia or a liquid aliphatic amine; tri(lower alkoxy)-aluminum compounds such as triisopropoxyaluminum; di(lower alkyl)-aluminum hydrides such as diethylaluminum hydride and diisobutyl-aluminum hydride; alkali metal-Group III-metal complex hydrides such as lithium aluminum hydride, sodium aluminum hydride, and sodium borohydride; tri(lower alkoxy)alkali metal-Group III-metal complex hydrides such as trimethoxy lithium aluminum hydride and tributoxy lithium aluminum hydride; diisobutyl aluminum hydride and the like. The alkali metal-Group III-metal complex hydrides are preferred as reducing agents, with the nonalkaline reagents, such as lithium aluminum hydride, being especially preferred.

This reaction is effected in any suitable inert reaction medium, such as hydrocarbons, e.g., cyclohexane, benzene, toluene, and xylene; ethers, e.g., diethyl ether, diisopropyl ether, and tetrahydrofuran. Protic solvents, such as water or alcohols, should not be employed when lithium aluminum hydride is the reducing agent, but can be employed with sodium borohydride.

The remaining reaction conditions are not narrowly critical, although it is generally preferred to effect the reduction at reduced temperatures, i.e., below about room temperature (about 20-25 C.). Temperatures in the range of from about 0 C. to about room temperature are normally employed.

In the reduction of a dienone of Formula Ia-l to a dienol of Formula Ia-Z any keto group in the side chain symbolized by Y is simultaneously reduced and any acyloxy group is hydrolyzed, in both cases yielding a corresponding hydroxy group. Any such side chain hydroxy group can be converted to an oxo moiety by treatment with conventional oxidizing means such as manganese dioxide. It is, however, preferable to use starting materials with etherified hydroxy moieties or ketalized oxo moieties in the side chain since these are unaffected by the reduction.

The free alcohol is recovered from the reaction mixture after treatment of the mixture with acid. The alcohol can be esterified in known manner, for example, by basecatalyzed reaction With a carboxylic acid halide or carboxylic acid anhydride. Illustrative bases includes inorganic bases such as sodium hydroxide and potassium hydroxide and organic bases such as a sodium alkoxide or an amine, especially a tertiary amine, and more particularly, pyridine and the picolines.

The ketodienes of Formula Ia-1 can also 'be converted to their 7,8-hydroxy-7a-hydrocarbyl derivatives represented by the formula:

wherein Y, R R R R and mare as previously defined and R is lower hydrocarbyl by reaction of the ketodiene with a Grignard reagent of the formula:

RnMgX (VII) wherein R is as previously defined and X is a halogen This Grignard reaction is conducted in known manner. For example, the Grignard reagent is prepared by reacting a hydrocarbyl halide with magnesium in an ether reaction medium, for example, ethyl ether or tetrahydrofuran, at elevated temperature, generally in the range of from about 40 C. to about 75 C. The ketodiene (Ia-1) is then added to the Grignard solution at about room temperature, although higher or lower temperatures can be employed. The resulting reaction product is hydrolyzed to produce the free alcohol, which can be esterified as discussed above.

Alternatively, the alcohols can be prepared by reaction of ketodiene (Ia-1) with ahydrocarbyl alkali metal compound such as methyl lithium, sodium acetylide, potassium acetylide, and the like.

If a dienone of Formula Ia-1 is to be converted to a diene of Formula Ia -3 then a starting material of Formula Ia-l wherein the side chain Y includes an oxo group should not be used. Also, during the course of such conversion any ester moieties present in the side chain will be hydrolyzed.

Illustrative examples of the dienes represented by Formulae Ia-2 and Ia3 include 3 ,6afl'dimethyl-7/3-hydroxy-23 ,5 ,6,6a,8-hexahydro- 1H- cyclopenta [f 1 benzopyran,

3,6a 8-diethyl-7firhydroxy-2,3,5,6,6a,8-hexahydro- 1H- cyclopenta [f] 1]benzopyran,

3-ethyl-6aB-metyhl-7fl-acetoxy-2, 3 ,5 ,6, 6a,8-hexahydro- 1H-cyclopenta[f] [l] benzopyran,

3 -ethyl-6 afl-methyl-7fi-benzoyloxy-2,3 ,5 ,6,6a,8-

hexahydrolH-cyclopenta- [f] l benzopyran,

3-ethyl-6a;8,7u-dimethyl-7 3-hydroxy-2,3,5,6,6a,8-

hexahydro-1H-cyclopenta[f] 1 ]benzopyran,

3 ,7 a-diethyl-6aB-methyl-713-hydroxyl-7 methyl-2,3 ,5, 6 ,6a,8-

hexahydro- 1 H-cyclopenta [f] 1 benzopyran,

3 -ethyl-6afi-methyl-7fi-hydroxy-7u-vinyl-2, 3 ,5 ,6,6a,8-

hexahydrolH-cyclopenta [f] l benzopyran,

' 3-ethyl-6aB-methyl-718-hydroxy-7wethynyl-2,3,5,6,6a,8-

hexahydro- 1H-cyclopenta [f] l benzopyran,

hexahydro-lH-cycolpenta [f] 1 benzopyran, 3-ethyl-6afi-dimethy1-7 8-hydroxy-l,2,3,5,6,6a,8,9-

octahydro-7H-naphtho [2,1-b] pyran,

3- 4-oxopentyl) -6afi-methyl-7fl-hydroxy-2,3 ,5 ,6,6a,8-

hexahydrolH-cyclopenta [f l benzopyran,

3-( 4-oxopentyl) -6ap-ethyl-7B-hydroxy-2,3,5,6,6a,8-

hexahydrolH-cyclopenta [f] 1 benzopyran,

3- 4,4-ethylenedioxy) pentyl] -6aB-methyl-7B-hydroxy- 2,3,5 ,6,6a,8-hexahydro-1H-cyclopenta [f] [1] benzopyran,

3 [4,4- 2',3 -'butylenedioxy-pentyl] -6ap-ethy1-7fihydroxy-2,3,5,6,6a,8-hexahydro-lH-cyclopenta [f] [1] benzopyran,

3- (4-t-butoxypentyl) 6a 3-methyl-7p-hydroxy-2,3,5,6,6a8-

hexahydro-1H-cyclopenta[f] 1 1 benzopyran,

3 (4-t-butoxypentyl) -6a/3-ethyl-7fl-hydroxy-2, 3, 5,6, 6a, 8-

hexahydro- 1 H-cyclopenta [f 1]benzopyran,

3 (4-hydroxypentyl) -6a,8-methyl-7fi-hydroxy-2,3 ,5 ,6,6a,8-

hexahydro- 1H-cyc1openta[f] 1 benzopyran and the like.

The second step of the general synthesis of the tricyclic compounds of this invention comprises conversion of the dienes of Formula Ia to the monoenes of Formula Ib by catalytic hydrogenation. Suitable catalysts include the noble metals, such as platinum, palladium, rhodium, and the like, as well as Raney nickel and other hydrogenation catalysts. These catalysts can be employed in the form of the metal alone, or can be deposited on suitable support materials, such as carbon, alumina, calcium carbonate, barium sulfate, and the like. Palladium and rhodium are preferred as catalysts. The hydrogenation is preferably conducted in the presence of inert solvents such as hydrocarbons, alcohols, ethers, and the like. The reaction conditions of pressure and temperature are not narrowly criitcal, and normally a hydrogen pressure of about one atmosphere and a temperature of about room temperature are employed. These ambient conditions are generally preferred to avoid significant hydrogenation of the 4a,9b(l0b)-double bond, although more severe conditions, for example, up to about 100 C. and up to about 100 atmospheres, can be employed if desired. The hydrogenation medium can be acidic, neutral, or basic, as may be desired, although neutral media, such as hydrocarbons, e.g., toluene or hexane, or basic media, such as an alcoholbase, e.g., methanol-sodium hydroxide, mixture are prefererd for best results. In general, hydrogenation of the diene of Formula Ia leads to the corresponding monoene of Formula Ib. However, in the event R is an unsaturated hydrocarbyl radical, the hydrogenation, in addition to hydrogenating the ring double bond, also hydrogenates the 7a-hydrocarbyl substituent, converting it to an alkyl Via the aforesaid catalytic hydrogenation C/D-trans compounds are formed in a major proportion when hydrogenating a diene of Formula Ia-2. This method thus provides an advantageous synthesis of C/D-trans steroidal materials. When hydrogenating a diene of Formula Ia1, C/D-cis compounds are formed in a major proportion. This method thus provides an advantageous synthesis of C/D-cis steroidal materials.

Compounds wherein Z is carbonyl, as represented by the formula:

(Ib-l) wherein Y, R R R and m are as previously defined,

can be converted to the corresponding alcohols or esters of the formula:

wherein Y, R R R R and m are as previously defined,

or to the 7,8-hydroxy-7a-hydrocarbyl compounds of the formula:

O I H by the technique discussed above regarding the dienes of Formula Ia.

When Z is carbonyl and the hydrogenation is effected under basic conditions, there is a tendency toward the production of predominantly the 6a/9a(10a) cis-compound; that is, the hydrogen atom in the 9a(l0a)-position of Formula Ib-l is predominantly in the S-orientation. When these compounds are intended as intermediates for the synthesis of steroids having the C/D-trans-orientation, this technique is not particularly desirable. Although the ratio of 5- to tat-orientation falls to about 1:1 at neutral conditions when hydrogenating a compound wherein Z is carbonyl, it is preferred to hydrogenate a 7,8-alcoh0l or ester of Formula Ia-2 because the products of this hydrogenation are predominantly the 6a/9a(10a)-trans-compounds. Compounds of Formula Ia3 when subjected to to the hydrogenation yield a ratio of 8- to u-orientation in between that of the compounds of Formula Ia-1 and that of the compounds of Formula Ia2. When monoenes of Formula Ib-l having C/D-trans configuration are desired, it is preferable to first reduce the dienone of Formula Ia-l to a corresponding hydroxy compound of Formula Ia-2 prior to the catalytic hydrogenation. Following the catalytic hydrogenation the carbonyl moiety in Formula Ib-l can be regenerated by conventional means, such as oxidation with chromium trioxide.

The monoene compounds of Formula Ib prepared by the above-described hydrogenation contain at least three asymmetric centers, at positions 3, 6a and 9a when m is one and at positions 3, 6a and 10a when m is two. With respect to these three centers there are thus eight antipodal configurations possible. By virtue of the unique asymmetric induction of this invention, proceeding from a racemic starting material of Formula 11, 1111 or Hb only four of these antipodes of Formula Ib are prepared and proceeding from an optically active starting material of Formula H, IIa or IIb only two of these antipodes of Formula Ib are prepared. Moreover, by the above-described hydrogenation of this invention and by appropriate selection of the 7-substituent in the diene of Formula Ia sub jected to the hydrogenation there can predominantly be prepared the desired 6a,9a(10a)-trans-stereo-configuration. Thus, the eventual obtention of the more desired 13fi-c/D-trans-configuration in the ultimate steroidal products is rendered more facile by the stereoselective reactions provided by this invention.

Illustrative examples of the monoenes of Formula Ib include 3,6aB-dimethyl-2,3,5,6,6a,8,9,9a-octahydrocyclopenta [f [1]-benzopyran-7 1H) -one,

3,6afl-diethy1-2,3,5 ,6,6a,8,9,9a-octahydrocyclopenta [f [1]-benzopyran-7 (1H)-one,

3,6afi-dipropy1-2,3 ,5 ,6,6a,8,9,9a-octahydrocyclopenta [f 1 [1]-benzopyran-7(1H)-one,

3,6afl-dimethyl-7B-hydroxy-2,3,5,6,6a,8,9,9a-octahydrolH-cyclopenta [f [1]-benzopyran,

3 ,afl-dimethyl-7fl-acetoxy-2,3 ,5 ,6,6a,8,9,9a-octahydrolH-cyclopenta [f] [1]-benzopyran,

3 ,6a5,7a-trimethyl-7 3-hydroxy-2,3 ,5 ,6,6a,8,9,9a-

octahydrolH-cyclopenta [f] l]benzopyran,

3,6a5,7a-triethyl-7fi-hydroxy-2,3,5,6,6a,8,9,9a-octahydro-1H-cyclopenta[f] 1 -benzopyran,

3 ,6a/3-dimethyl-l,2,3,5,6,6a,8,9,10,10a-decahydro-7H- naphtho- [2, l-b] pyran-7-one,

3- (4-oxopentyl) -6ae-methyl-2,3,5,6-6a,8,9,9a-octahydrocyclopenta [f] 1]benzopyran-7( 1H) -one,

3- (4-oxopentyl) -6aB-ethyl-2,3,5,6,6a,8,9,9a-octahydrocyclopenta [f 1]benzopyran-7( 1H) -one,

3-[ (4,4-ethylenedioxy) pentyl] -2,3,5,6,6a,8,9,9a-octahydrocyclopenta[f] [l]benzopyran-7( 1H) -one,

3- (4-t-butoxypentyl) -2,3 ,5 ,6,6a,8,9,9a'octahydrocyclopenta [f [1]benzopyran-7(1H)-one,

3- (4-hydroxypentyl) -2,3,5,6,6a,7,8,9,9a-octahydrocyclopenta- [f] 1]-benzopyran-7( 1H) -one, and the like.

The final reaction of applicants general process for the compounds of this invention is the conversion of the monoene of Formula Ib to the perhydro compound of Formula Ic by reaction of the monoene with a compound having the formula:

wherein R is as previously defined.

That is, the monoene of Formula Ib is reacted with water, a primary alcohol, or a carboxylic acid. This reaction is catalyzed by mineral or organic acids, for example, hydrochloric acid, phosphoric acid, sulfuric acid, paratoluenesulfonic acid, and the like. Sulfuric acid is the preferred acid catalyst, and water the preferred reactant. Although not necessary, it is desirable to conduct this reaction in the presence of an added solvent, particularly in the event the compound of Formula VIII is water. In this case, it is desirable to employ a solvent which is both miscible with water and a solvent for the monoene of Formula Ib. Solvents of this nature include acetone, tert.- butanol, dioxane, and the like. The reaction temperature is not critical, and ambient temperature is normally employed, although higher and lower temperatures could be employed if desired.

In addition to the addition of the R OH compound, this step effects the conversion of a ketalized side chain such as the 3-[(4,4-alkylenedixoy)pentyl]-group, if present, to the 3-(4-oxopentyl)-group.

As with the compounds of Formulae Ia-l and Ib-l, the compounds of general Formula 10 wherein Z is carbonyl:

(VIII) YCHz b Ru wherein Y, R R R R and m are as previously defined,

H um R12 (Ia-2) wherein Y, R R R R R and m are as previously defined,

or the fi-hydroxy-a-hydrocarbyl compounds:

wherein Y, R R R R R12, R and m are as previously defined,

by the previously described methods.

In a modification of the general technique outlined above, one can simultaneously effect the hydrogenation and hydration steps, for example, by hydrogenation of a diene of formula Ia in aqueous sulfuric acid. When this simultaneous hydrogenation-hydration reaction is effected, it is preferred to begin with a diene having a hydroxyl group in the 7p-position.

Illustrative examples of the compounds falling within the scope of Formula include 3,6afl dimethyl 4a,7;3 di (acetoxy) perhydrocyclopenta[f] [1]-benzopyran,

3,6ap dimethyl-4a,75 di (acetoxy perhydro 3H-naphtho [2,1-b]pyran,

3 (4-oxopentyl) -6aB-methyl-4a-hydroxyperhydrocyclopenta[f] [l]benzopyran-7-one,

3- 4,4-ethylenedioxy pentyl] -6a,8-methyl-4a-hydroxyperhydrocyclopenta [f] 1 benzopyran7-one,

3- (4-t-butoxypentyl) -6a,8-methyl-4a-hydroxyperhydrocyclopenta [f ]l 1]benzopyran-7-one,

3 (4-hydroxypentyl) -6a/3 methyl 4a-hydroxyperhydrocyclopenta [f l]benzopyran-7-one,

and the like.

Although in the various compounds of Formula I, as well as their precursors of Formulas II, IIa and III), the symbol Y comprehends a 3-oxobutyl moiety, it should be noted that it is not preferred to work directly with such oxo-substituted compounds. This is because in many of the reaction steps utilized herein such an oxo moiety would itself be affected. Accordingly, it is preferred to protect such an oxo moiety and regenerate the oxo moiety from its protected form at any desirable stage of the reaction sequence. Protection of the oxo moiety can be effected according to means known per se. Similarly, regeneration of the oxo moiety from its protected form can be eifected by means known per se. Thus, one preferred method of effecting protection of the oxo moiety is to convert it to its ketal by reaction with an alkanediol in a known manner. Advantageous results are obtained where protection of the oxo moiety is effected at an early stage in the synthesis. An especially preferred alkanediol is butanediol which affords excellent resistance to attack by nucleophilic reagents. When butanediol is employed, R and R when taken together are for example, 2,3-b utylenedioxy. Similarly, an oxo moiety can be converted to its dithia ketal by reaction with dithioethane in a known manner, for example, in acetic acid at room temperature and in the presence of boron trifluoride. Moreover, a monothia ketal can similarly be prepared in a known manner, for example, by reaction of the oxo moiety with Z-mercaptoethanol in dioxane at room temperature in the presence of zinc chloride and sodium sulfate. Also, the monoaza ketals can be prepared in a known manner, for example, by reaction of the oxo moiety with 2-hydroxyethylamine in the presence of acid. Finally, the oxo moiety can be reduced to the corresponding hydroxy compound which can than be etherified or esterified. As indicated above, the oxo moiety can be regenerated from its protected form at any desired stage of the reaction sequence. Thus, it can be readily produced by hydrolysis of the alkylenedioxy ketals in a known manner. Similarly, it can be regenerated from the dithia ketal in a known manner, for example, by treatment with phenylmercuric chloride and calcium carbonate in ethanol or by treatment with dioxane in methanolic hydrochloride. Also, it can be regenerated from a monothia ketal in a known manner, for example, by treatment under strong acidic conditions, for example, by treatment with aqueous sulfuric acid in dioxane or hydrochloride in acetic acid. Moreover, it can be regenerated from a monoaza ketal in a known manner, for example, by treatment with a strong aqueous acid. Also, ethers and/or esters can be reconverted to the free hydroxy group which in turn can be oxidized to give the oxo moiety.

As indicated above, the tricyclic compounds of this invention are useful as intermediates for the preparation of various steroid compounds, depending upon the nature of Y. For example, compounds wherein Y is R and R is hydrogen or alkyl lead to 9B,10a-steroids or wot-steroids, whereas compounds wherein R is B-substituted-butyl, lead to 19-nor-steroids of the normal series, as illustrated by the following reaction scheme.

In the first step of this reaction scheme, the compound of Formula la is oxidized to form bicyclic compound of the 65 Formula X wherein Y is hydrogen, alkyl, 3-alkylenedioxybutyl, the monothia, monoaza or dithia chlcogen thereof or etherified S-hydroxybutyl, by contract with such oxidizing agents as chromic acid, potassium dichromate,

or potassium permanganate. Jones reagent (chromic acid, 70

sulfuric acid and acetone), or a chromic acid-acetic acid mixture are preferred as oxidizing agents. The nature of Z is unchanged in this reaction, except when Z is hydroxymethylene [-CH(OH)]. In this instance, unless the hydroxyl group is protected, as by formation of a lower 7 acyl ester, it is oxidized to form a carbonyl group. Similar oxidation is effected when compound (10) contains as Y a B-hydroxybutyl group. A hydroxylated product is readily obtained, however, by hydrolysis of a product ester. The reaction temperature is not narrowly critical, and temperatures in the range of from 0 C. to about 75 C. are suitable, although ambient temperatures are preferred.

In the second step, bicyclic compound (X) is treated with acid or base to effect cyclization to (XI). In this reaction, it is preferred that the water of reaction be removed, as by refluxing the reaction mixture with an azeotroping agent in the presence of a strong acid and sepa- 1 9 rating the water from the condensate. Suitable strong acids are sulfuric acid, p-toluenesulfonic acid, potassium bisulfate and the like. Alternatively, base catalyzed dehydration can be utilized, for example, by refluxing compound (X) in the presence of methanolic sodium hydroxide.

'Ihe hydrogenation of cyclo-olefin (XI) to tricyclic compounds (XV) or (XII) is preferably effected with a noble metal catalyst, e.g., a palladium-charcoal catalyst or a rhodium catalyst. In Formula XV, R represents hydrogen or alkyl. Thus, when compounds of Formula XI wherein Y represents hydrogen or alkyl are hydrogenated, compounds of Formula XV are obtained, whereas when compounds of Formula XI wherein'Y represents a .3-substituted butyl radical of the formula hydrogenation yields compounds of Formula XII. Hydrogenation products of Formula XI are converted to retorsteroids by base catalyzed reaction with methyl vinyl ketone to yield a, 9B,10a-androst-4-ene-3-one of Formula XVIH. The conversion of compounds of Formula XI to compounds of Formula XV and of the latter to compounds of Formula XVIII are described in greater detail in Belgian Pat. No. 663,197.

Compounds of Formula XI wherein Y is R can also be directly reacted with methyl vinyl ketone yielding a S-hydroxy-tetracyclic compound of Formula XVI. These latter compounds can then be subjected to dehydration followed by hydrogenation or to hydrogenation followed by dehydration to yield 9,3,10ocor 10a-steroids of Formulas XVII and XVIII. These procedures are described in greater detail in Netherlands Octrooiaanvrage No. 6412939. Still other methods of utilizing compounds of Formula XI are described in the literature and other patents.

In those compounds of Formula XI wherein Y is a 3- substituted butyl radical, catalytic hydrogenation over a noble metal catalyst such as palladium gives a 19-nor-4,5- seco compound of Formula XII. The 3-substituted butyl radical is then converted to a 3-oxobutyl radical, thus giving a compound of Formula XHI.

The conversion of the 3-substituted butyl radical of the compound of Formula XH to the 3-oxobutyl radical of the compound of Formula XIII can be effected for each particular meaning of R and R in a manner known per se as described hereinabove for generation of a 3-oxobutyl moiety in compounds of Formula I. When R and R taken together are alkylenedioxy, the conversion of compounds of the Formula XII to compounds of the Formula XIII proceeds directly in the presence of acid, e.g., hydrochloric acid or sulfuric acid and acetone at room temperature.

However, the conversion of the 3-substituted butyl radical of the compounds of Formula XII to the 3-oxo-butyl radical of the compounds of Formula XIII for other specifiedvalues of R and R defined hereinafter, proceeds through a reaction sequence which yields novel intermediates. When R taken alone is R R is lower alkyl (i.e., when R is lower alkoxy) and R taken alone is hydrogen; compounds of Formula XH, for example, 10 [3 tertiary-butoxy-butyH-l8-methyl-19-nor-desA-androstan-5,17-dione, can be converted by cyclization to a novel class of enol ethers of the formula:

wherein R R R R and R are each independently hydrogen or lower alkyl; R is a primary alkyl group of from 1 to 5 carbon atoms; In is an integer having a value of from 1 to 2; and Z is defined as aforesaid.

Exemplary of the compounds of this formula is 6a,9atrans-2-methyl-6aB-ethyl-7-oxo 3,4,5a,10a,5,6,8,9,l0,lldecahydro 2H,7H cyclopenta[5,6]naptho[2,1-b]pyran. Cyclization to the enol ether of Formula XlX can be effected by treatment of the alkoxy substituted derivatives of Formula XII with acid and heat in a solvent such as for example, benzene or toluene. Suitable acids for the cyclization step are p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, potassium bisulfate and the like. This cyclization is preferably effected at the reflux temperature of the reaction medium although temperatures from between 70 to are suitable.

Further reaction of this novel class of enol ethers by hydration with acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid and the like, in a solvent at room temperature yields hydroxy-ether compounds of the formula:

I Rn O H E wherein R R R R and R are each independently hydrogen or lower alkyl; R is a primary alkyl group of from 1 to 5 carbon atoms; m is an integer havinga value of from 1 to 2; and Z is defined as aforesaid.

Suitable solvents for this reaction include acetone, methanol, ethanol and the like. Examplary of compounds of this formula is 6a,9a-trans-2-methyl-6aB-ethyl-7-oxo-perhydrocyclopenta [5 ,6] naphtho 2,1-b] pyran-l la-ol.

The hydroxy-ether compounds, can be further reacted by an oxidation process to produce the diketone compounds of structure (XIII). Moreover, where R in Formula X is ethyl, i.e., 6a,9a-trans-2-methyl-6a/8-ethyl-7- oxo-perhydrocyclopenta[5,6]naphtho[2,l b]pyran-lla ol, the oxidation reaction affords the novel compound 10 [3-oxo-butyl1-18-methyl l9 nor-desA-androstan-5,17- dione. Exemplary of the suitable oxidizing agents for the reaction, are chrornic acid and potassium dichromate. Jones Reagent (chromic acid, sulfuric acid and acetone) is an especially preferred reagent for this purpose. The reaction is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid at room temperature.

Cyclization of the compounds of Formula XIII can then be effected to yield l9-nor-androst-4-ene-3-one of the Formula XIV. The cyclization reaction of compounds of Formula XHI to compounds of Formula XIV can be effected by treatment of the compound of Formula XIII with acid or base. In this reaction it is preferred that the water of reaction be removed, as by refluxing the reaction mixture with an azeotroping agent in the presence of a strong acid and separating acid, p-toluenesulfonic acid, potassium bisulfate and the like. Alternatively, basecatalyzed dehydration can be utilized, for example, by heating compound (XIII) in the presence of methanolic sodium hydroxide or potassium t-butylate in t-butanol to about 50 C. Moreover, where R in Formula XHI is ethyl, for example, 10-[3-oxo-butyl]-18methyl-19-nordesA-androstan-S,l7-dione, the cyclization process yields the novel 18-homo di-keto compound l3fl-ethyl-gon-4- ene-3,17-dione.

Compounds of Formula XIV can be selectively alkynylated by a suitable organo metallic acetylide affording norgestrel (13fl-ethyl-l7a-ethinyl-l7-hydroxy-gon-4-ene-3- one). Exemplary of the suitable alkynylating agents to effect the conversion to norgestrel are the alkali acetylides such as lithium acetylide, potassium acetylide, sodium acetylide, etc. The reaction is carried out in the presence of liquid ammonia in a suitable solvent system such as for example, benzene or toluene. The alkynylation is effected preferably at the reflux temperature of the reaction medium although temperatures from between 60 to 30 are suitable. Exemplary of other suitable reagents to effect the acetylenic addition are lithium acetylide ethylenediamine complex in a dirnethylformamide solvent and Grignard analogs such as mono and his acetylene-magnesium halides. The acetylene addition, known With 13-methyl-substituted steroids, is similarly effected with the more bulky 13-ethyl-substituted steroid notwithstanding the increased steric hindrance in the latter configuration.

The above and other methods for utilizing compounds of Formulas XII and XIII as intermediates in syntheses of steroidal materials are described in published patents and in the literature, such as French Patent Nos. 1,364,566, 1,452,898, 1,432,569 and 1,465,400.

Compounds of Formulas XI, XIV, XVII, XVIII, XIX and XX wherein Z is carbonyl can be converted into corresponding pregnane compounds, i.e., compounds in which Z is of the formula by known procedures. Thus, for example, 19-nor-14{3 androst-4-ene-3,l7-dione can be converted into 19-nor- 145,17a-prgesterone and desA-androst-9-ene-5,17-dione can be converted into desA-pregn-9-en-5-one. These procedures for converting androst-17-ones into pregnanes are best effected if all carbonyl groups other than that in the 17-position are initially protected.

As has been pointed out above, the products of this invention are produced in the form of various optically active antipodes, which can be carried through the entire reaction sequence, or which can be resolved at suitable places during the reaction sequence. For example, at any stage wherein a compound having a secondary hydroxyl group is present, such as hydroxytetrahydropyran (IV), or any of the hydroxy compounds of Formula I, one can react the secondary alcohol with a dicarboxylic acid to form a half-ester. Suitable dicarboxylic acids include lower alkyl dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, or aromatic carboxylic acids such as phthalic acid. The resulting halfester is then reacted with an optically active base, such as brucine, ephedrine, or quinine, to produce a diastereomeric salt. The salts, after separation, are then readily reconverted to optically active alcohols. As an alternative, the secondary alcohol can be reacted with an optically active acid, for example, camphorsulfonic acid. The resulting diastereomeric esters are then separated and reconverted to the alcohols.

It is preferred that the resolution be effected at some stage in the synthesis of alken-3-one, as by the abovementioned resolution of hydroxytetrahydropyran (IV). In a more preferred technique, optically active S-alkyl-S- valerolactone is obtained from 5-alkyl-5-oxopentanoic acid via known microbiological processes. The S-form of this lactone is the preferred form for use in accordance with this invention. In a third method, the racemic lac-- tone can be hydrolyzed to the corresponding hydroxy acid, which is then resolved by treatment with an optical y active base in the manner described above. Still other methods will be apparent to those skilled in the art. Resolution at such early stages in the overall process described herein is highly preferred because of the improved efficiency in the production of steroids having a desired stereo-configuration. Because the stereoconfiguration is retained throughout the synthesis of alken-3- one (II), and further, because the condensation of alken- 3-one or variant (H, 1111 or IIb) with cycloalkanedione (III) is stereo-specific, one, by proper selection of stereoisomers at these early stages, can ensure that substantially all of the tricyclic compounds of this invention and the steroids derived therefrom have a selected stereo-configuration. Thus, by this technique, the production of compounds of the undesired configuration is minimized or prevented entirely, with an attendant increase in the efiiciency of the production of compounds of the desired configuration.

In the claims, all compounds shall be construed to include, independently, the racemic form of the compound and independently, each enantiomeric form, i.e., the d and 1 configurations unless specifically indicated otherwise.

The following examples are illustrative. All temperatures are in degree centigrade and all products having centers of asymmetry are racemic unless specifically indicated otherwise.

EXAMPLE 1 (a) A mixture of 38 grams of Z-methylcyclohexane- 1,3-dione, 51 grams of sodium hydroxide, and 450 milliliters of water was hydrogenated over Raney nickel catalyst at a maximum temperature of 140 C. and a maximum pressure of 750 p.s.i. The reaction mixture was filtered and the filtrate, containing sodium S-hydroxyheptanoate, was acidified with concentrated hydrochloric acid (to a pH of 1), and then refluxed for 30 minutes. The resulting solution was cooled and filtered. The filtrate was extracted with three l-liter portions of benzene and the combined benzene extracts, after washing with water, drying over sodium sulfate, and evaporation, yielded 26 grams of 5-ethyl-5-hydroxyvaleric acid lactone.

(b) A suspension of 5.2 grams of lithium aluminum hydride in 250 milliliters of anhydrous ether was added with stirring over one hour to a solution of 64 grams of ;5-ethyl-5-hydroxyvaleric acid lactone in 500 milliliters of anhydrous ether maintained at 05 C. and under a nitrogen atmosphere. After the addition of 250 milliliters of 3 N sulfuric acid, the reaction mixture was extracted with three IOU-milliliter portions of ether. The combined ether extracts were then washed with two -milliliter portions of sodium bicarbonate solution, then with two 15 O-milliliter portions of water. After drying over sodium sulfate, the etheric solution was evaporated at 45 C. under vacuum to yield 57.1 grams of 6-ethyl-2-hydroxytetrahydropyran.

(c) To 7.6 grams of magnesium in 7 milliliters of anhydrous tetrahydrofuran containing a few drops of ethyl bromide and a few milligrams of iodine maintained at 45-48 C. was added, over a four-hour period, milliliters of a 20.8 weight percent solution of vinyl chloride in tetrahydrofuran. The resulting reaction mixture was cooled to 30 C. and a solution of 13 grams of 6-ethyl-2-hydroxytetrahydropyran in 40 milliliters of tetrahydrofuran was added. After standing overnight, there was added ice and ammonium chloride. Extraction of the resulting mixture with three 250-milliliter portions of ether, washing with three IOU-milliliter portions of sodium chloride, drying over sodium sulfate, and evaporation gave 16 grams of 3,7-dihydroxy-1-nonene.

(d) To a solution of 25 grams of 1-nonene-3,7-diol in 1250 milliliters of 1,2-dichloroethane was added 0.25 gram of hydroquinone and 300 grams of manganese dioxide. The resulting slurry was stirred vigorously for one hour without heating, during which time the reaction temperature rose to about 30 C. The resulting reaction mixture was filtered and the manganese dioxide filter cake was washed thoroughly with 500 milliliters of 1,2-dichloroethane. The combined filtrates were evaporated in vacuo at 40 C. to yield 17.3 grams of 7-hydroxy-l-nonen- 3-one. This compound is reacted with hydrogen chloride to produce 1-chl0ro-7-hydroxynonan-3 -one, with dimethylamine to produce l-(N,N-dimethylamino)-7-hydroxy-3- one, with water to produce 1,7-dihydroxynonan-3-one,

23 or with ethanol to produce 1-ethoxy-7-hydroxynonan-3- one.

EXAMPLE 2 Employing procedures similar to those described in Example 1, except that cyclohexane-1,3-dione is substituted for Z-methylcyclohexane-1,3-dione, 7-hydroxyoct-len-3-one is produced.

EXAMPLE 3 Employing procedures similar to those described in Example 1, except that 2-ethylcyclohexane-1,3-dione is substituted for Z-methylcyclohexane-l,3dione, 7-hydroxydec- 1-en-3-one is produced.

EXAMPLE 4 A 20 percent solution of diisobutyl aluminum hydride in 31.4 milliliters of toluene was added over a 30-minute period to a solution of 5 grams of L-(-)-5-pentyl-5-hydroxy-valericacid lactone in 50 milliliters of toluene at 70 C. After workup of the resulting reaction mixture as described in Example 1(b), there was obtained 5 grams of practically pure optically active 6-pentyl-2-hydroxytetrahydropyran.

To a solution of this product in 20 milliliters of tetrahydrofuran was added at 30 C. a solution of vinyl magnesium chloride in tetrahydrofuran prepared from 3.5 grams of magnesium and excess vinyl chloride in the manner described in Example 1(c). After hydrolysis of the reaction product with an ammonium chloride-ice mixture, followed by extraction with ether, there was obtained 5.72 grams of 3(R,S),7(S)-dihydroxy-1-dodecene as an oil. After crystallization from isopropyl ether-pentane at C., the diol melted at 65.5-67.5 C. and had an optical rotation [a] =|5.9 as determined from a 1 percent solution in chloroform.

A solution of 5.22 grams of the diol in 1,2-dich1oroethane was stirred with 63 grams of manganese dioxide in'the presence of 50 milligrams of hydroquinone for one hour. After filtration to remove the manganese dioxide, washing with additional dichloroethane and ether, and evaporation of the filtrate at 30 C., there was obtained 3.98 grams of optically active 7(S)-hydroxy-1-dodecen-3- one.

EXAMPLE A solution of racemic 7-hydroxy-1-nonen-3-one [21.3 g.; crude obtained as in Example 1(d)] in hexane (200 ml.) was treated for 15 hours at 25 C. with a solution of (-)-a-phenylethylamine (11.5 g.) in hexane (115 ml.). The reaction mixture was then purified by chromatography on alumina (660 g.). Elution with hexane first gaveupolar by-products. Hexane-ether-(4: l)-, (1:1), and straight ether then eluted 2-[2-(1-phenylethylamino)- ethyl]-6-ethy1-Z-tetrahydropyranol obtained in solid from after evaporation of the solvents.

EXAMPLE 6 To 20 g. of magnesium turnings in a 500 ml. flask equipped with Dry-Ice condenser, thermometer, and dropping funnel, 30 ml. of tetrahydrofuran was added followed by dropwise addition of vinyl chloride solution 200 ml.; 26% solution in tetrahydrofuran) while the oil bath in which the flask was immersed was maintained at 70. The vinyl chloride was added at such' a rate so that the reaction temperature remained at 46-52. Iodine vapor and methyl iodide were used to initiate the reaction.

Upon completion of the addition of the vinyl chloride, the reaction mixture was cooled to -5 and 6-[4,4-ethylenedioxy)-pentyl]-tetrahydrofuran-2-ol (44.63 g.) dissolved in 150 ml. tetrahydrofuran was added dropwise to the Grignard reagent at 5 to 0. The resulting mixture was stirred overnight at room temperature.

The solution was then treated with ice and ammonium chloride solution (200 ml.), and the mixture extracted three times, each time with 500 ml. of chloroform. The organic phase was washed once with ammonium chloride solution and twice with water, and then dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded crude 11,11-ethylenedioxy-3,7-dihydroxyl-dodecene as pale yellow liquid which solidified upon refrigeration.

A sample of the crude product was recrystallized once from isopropyl ether-hexane to give clusters of colorless needles which upon three additional recrystallizations from the same solvent provided 11,ll-ethylenedioxy-3,7- dihydroxy-l-dodecene which melted at 52-54.

A solution of 22.0 g. of 11,1l-ethylenedioxy-l-dodecene-3,7-diol in benzene (600 ml.) and diethylamine (40 ml.) was treated under vigorous stirring with manganese dioxide (108 g.) at 25 C. After stirring for 18 hours at room temperature, the manganese dioxide was filtered off and washed with benzene. After evaporation of the filtrate crude 2-(2-diethylaminoethyl)-6-(4,4-ethylenedioxypentyl)-2-tetrahydropyranol was obtained.

A sample of the crude 11,1l-ethylenedioxy-3,7-dihydroxy-l-dodecene (10 g.; prepared as described above) was dissolved in dichloroethane (250 ml.), and to this solution activated manganese dioxide (60 g.) was added. The mixture was stirred for 1 hour at room temperature, filtered, and the filter cake washed three times, each time with 250 ml. of dichloroethane. Concentration of the combined filtrate afforded crude 11,11-ethyleuedioxy-7-hydroxy-l-dodecen-S-one.

EXAMPLE 8 A mixture of 8.3 grams of 7-hydroxy-l-nonen-3-one, 7 grams of Z-methylcyclopentane-1,3-dione, 0.1 gram of hydroquinone, 4.2 milliliters of pyridine, and 42 milliliters of toluene was refluxed under a nitrogen atmosphere for two hours employing a Dean-Stark water-collection apparatus. The reaction solution, after cooling, was filtered to recover unreacted 2-methylcyclopentane-1,3-dione. The filtrate was evaporated to dryness, yielding 9.78 grams of crude 3 ethyl Gafi methyl 2,3,5,6,6a,8 hexahydrocyclopenta[f] [l]benzopyran-7(lH)-one. A mixture of the crude product, 1 gram of charcoal, and milliliters of ether was refluxed for 5 mintues. After decantation, the resulting solution was concentrated and 20 milliliters of hexane was added to cause crystallization. A first crop of 3.88 grams was obtained which melted at 9699 C. After concentration of the mother liquor and crystallization from a cold diisopropyl ether/hexane mixture, a second crop of crystals melting at l00l03 C. was obtained.

Employing similar procedures 3-ethyl-6aB-methyl-2,3, 5,6,6a,8 hexahydrocyclopenta[f] [l]benzopyran 7(1H)- one is prepared by substituting 1-chloro-7-hydroxynonan-3-one for the 7-hydroxy-l-nonen-3-one.

EXAMPLE 9 A mixture of 16.2 grams of 7-hydroxy-1-nonen-3-one, 11.5 grams of 2-methylcyclopentane-1,3-dione, 210 milliliters of xylene, and milliliters of acetic acid was refluxed for 1% hours. After evaporation, the crude reaction product, weighing 27.9 grams, was extracted with two -milliliter portions of benzene. The remaining residue, which weighed 1.7 grams, was unreacted Z-methylcyclopentane-l,3-dione. The benzene extracts were combined and evaporated to yield 25 grams of crude product. A

25 solution of this product in hexane was filtered through alumina and, after evaporation of the hexane and crystallization of the product from a hexane-pentane mixture, there was obtained 16.6 grams of 3-ethyl-6aB-rnethyl- 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran 7 (1H)-one, melting point '4106 C.

Employing similar procedures 3-ethyl-6a[3-methyl-2,3, 5,6,6a,8 hexahydrocyclopenta [f] [1]benzopyran 7(1H) one is prepared by substituting 1-(N,N-dimethylamino)-7- hydroxynonan-Ii-one for the 7-hydroxy-1-nonen-3-one.

EXAMPLE 10 A mixture of 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12 grams of Z-methylcyclopentane-l,3-dione, and 50 milliliters of toluene was refluxed for 6 hours. Workup of the reaction mixture in the manner described in Example 9 yielded 3-ethyl-6afl-methyl-2,3,5,6,6a,8-hexahydrocyclopenta [f] [1]benzopyran-7(1H)-one.

EXAMPLE 1 1 A mixture of 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12 grams of 2-methylcyclopentane-1,3-dione, 16 milliliters of p-dioxane, and 80 milligrams of p-toluenesulfonic acid was reacted at 25 C. for 22 hours. Employing the work-up procedures of Example 9, there was obtained 3-ethyl-6afi-methyl 2,3,5,6,6a,8 hexahydrocyclopenta [f] [1]benzopyran-7(1H)-one.

EXAMPLE 12 A mixture of 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12 grams of Z-methylcyclopentane-1,3-dione, 0.16 grams of p-toluenesulfonic acid, and 16 milliliters of benzene was refluxed for 30 minutes and worked up as described in Example 9 to yield 3-ethyl-6a5-methyl-2-3,5, 6,6a,8 hexahydrocyclopenta[f] [1]benzopyran 7(1H)- one.

EXAMPLE 13 A mixture of 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12 grams of 2-methylcyclopentane-1,3-dione, 16'milliliters of toluene, 0.8 milliliter of pyridine, and 0.16 gram of p-toluenesulfonic acid was refluxed for 30 minutes. After treatment of the reaction mixture as described in Example 9, there was obtained 3-ethyl-6a 3-methyl-2,3,5, 6,6a,8 hexahydrocyclopenta[f] [1]benzopyran 7(1H)- one.

EXAMPLE 14 A mixture of 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12 grams of 2-methylcyclopentane-1,3-dione, 25 milliliters of toluene, 5 milliliters of cyclohexanone, and 0.3 gram of aluminum isopropoxide was refluxed under a nitrogen atmosphere for one hour. After workup as described in Example 15 below, there was obtained 3-ethyl- 6aB methyl 2,3,5,6,6a,8 hexahydrocyclopenta[f] [1] benzopyran-7(1H)-one, melting point IOU-102 C.

EXAMPLE 15 A mixture consisting of 1.56 grams of 7-hydroxy-lnonen-3-one, 1.12 grams of 2-methylcyclopentane-l,3- dione, and 0.16 gram of potassium acetate in tert.-butanol, was held at 25 C. for hours. The resulting reaction mixture was extracted with three 200-milliliter portions of ether. After washing each ether extract with three 100- milliliter portions of water, the ether extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The residue which weighed 2.16 grams was dissolved in 22 milliliters of hexane and chromatographed on alumina. After elution with hexane and evaporation of the hexane, there was obtained spiro[4a-methyl-7ahydroxy 2,3,4,4a,5,6,7,7a octahydrocyclopenta[b] pyran-S one 2,2 (6-ethyltetrahydropyran)], melting point 889S C. The melting point was 93-97 C. after sublimation at 65 C. and 0.01 mm.

EXAMPLE 16 A mixture of 0.3 gram of 7-hydroxy-1-nonen-3-one, 0.3

gram of 2-methylcyclopentane-1,3-dione, 6 milliliters of tert.-butanol, and 15 milligrams of sodium hydroxide was held at 25 C. for 2 /2 days yielding spiro[4a-methyl-7ahydroxy-2,3,4,4a,5,6,7,7a octahydrocyclopenta[b]pyran- 5-one-2,2'-(6-ethyltetrahydropyran)1. The same product was obtained when potassium hydroxide was substituted for sodium hydroxide.

EXAMPLE 17 EXAMPLE 18 A mixture of milligrams of spiro[4a-methyl-7ahydr0xy-2,3,4,4a,5,6,7,7a octahydrocyclopenta[b]pyran- 5-one-2,2'-(6-ethyltetrahydropyran)], 5 milliliters of benzene, and 10 milligrams of p-toluenesulfonic acid was held at 25 C. for 20 hours. After workup in the manner described in Example 15 and crystallization from hexane, there was obtained pure 3-ethyl-6aB-methyl-2,3,5,6,6a,8- hexahydrocyclopenta [f] [1]benzopyran-7 1 H) -one.

EXAMPLE 19 Employing apparatus and procedures similar to those described in Example 8, except that Z-ethylcyclopentane- 1,3-dione is substituted for 2-methylcyclopentane-1,3- dione, there is produced 3,6aB-diethyl-2,3,5,6,6a,8-hexahydrocyclopenta[f] [1]benzopyran-7(lH)-one melting at 5759 C.

EXAMPLE 20 Employing apparatus and procedures similar to those described in Example 8, but substituting Z-methylcyclohexane-1,3-dione for Z-methylcyclopentane-1,3-dione, there is produced 3-ethyl-6afl-methyl-1,2,3,5,6,6a,8,9- octahydro-7H-naphth0[2,1-blpyran-7-one melting at 91- 92 C.

EXAMPLE 21 Employing apparatus and procedures similar to those described in Example 8, but substituting 2-ethylcyclohexane-1,3-dione for Z-methylcyclopentane-l,3-dione, there is produced 3,6aB-diethyl-1,2,3,5,6,6a,8,9-octahydro- 7H-naphtho[2,1-blpyran-7-one.

EXAMPLE 22 Employing apparatus and procedures similar to those described in Example 8, but substituting 7-hydroxy-1- octen-3-one for 7-hydroxy-1-nonen-3-one, there is produced 3,6a,6' dimethyl-2,3,5,6,6a,S-hexahydrocyclopenta [f] [1]benzopyran-7 (1H)-one.

EXAMPLE 23 Employing apparatus and procedures similar to those described in Example 19, but substituting 7-hydroxy-1- octen-3-one for 7-hydroxy-1-nonen-3-one and 2-ethylcyclopentane 1,3 dione for Z-methylcyclopentane-1,3- dione, there is produced 6a/i-ethyl-3-methyl-2,3,5,6,6a,8- hexahydrocyclopenta [f] [1]benzopyran-7(1H)-one.

EXAMPLE 24 Employing apparatus and procedures similar to those described in Example 8, but substituting 7-hydroxy-1- decen-3-one for 7-hydroxy-1-nonen-3-one, there is produced 6afi methyl-3-propyl-2,3,5, 6,6a,8-hexahydrocyclopenta[f] [1]benzopyran7(1H)-one.

EXAMPLE 25 A mixture of the optically active 7-hydroxy-1-dodecen- 3-one, obtained as described in Example 4, 2.25 grams of Z-rnethylcyclopentane-l,3-dione, 50 milliliters of xylene, and 25 milliliters of acetic acid was refluxed for 1 /2 hours under a nitrogen atmosphere. After evaporation under vacuum, the residue was extracted with cold benzene leaving 400 milliliters of unreacted methylcyclopentanedione as an insoluble residue. The benzene solution was then evaporated to yield 5.56 grams of optically active 3-pentyl-6a/3-methyl-2,3,5,6,6a,8-hexahydrocyclopenta[f] [l]-benzopyran-7( 1H) -one. After chromatographing the crude product on alumina, followed by crystallization from methanol-water, the product melted at 60-61" C., [a] 166.

EXAMPLE 26 A mixture of Z-methyl-cyclopentane-l,3-dione (2.24 g.), xylene (100 ml.) and glacial acetic acid (25 ml.) was refluxed under a nitrogen atmosphere for 2 minutes. Then optically active 2'[2-(l-phenylethylamino)ethyl]- .6-ethyl-2-tetrahydropyranol oxalate (6.4 g., prepared as described in Example 6) was added and the mixture refluxed for 1 hour. The resultant solution was then washed with H O (2x50 ml.), saturated NaHCO solution (2X50 ml.) and H (1X50 ml.). The aqueous phases were extracted with benzene (2x150 ml.). The combined benzene and xylene fractions were evaporated and the residue (2.4 g.) was chromatographed on alumina (160 g.). With hexane and hexan-ether-(19z1) (total 13 fractions, 160 ml. each) pure- 3 ethyl 6a;3 methyl- 2,3,5,6,6a,8 hexahydro cyclopenta[f] [l]benzopyran-7 (1H)-one was eluted. After evaporation of fractions 3-11 (pure by thin layer chromatography analysis) yellow crystals resulted. This product had a rotation of [a] -145.3 (c=1.0; CHCl Recrystallization from pentane alforded 3-ethyl-6af3-methyl-2,3,5,6,6a,8-hexahydro-cyclopenta[f][1]benzopyran 7(1H) one as beige crystals, M.P. 97-100", -145.7 (c=1.0; CHCl EXAMPLE 27 A mixture of Z-methyl-cyclopentane-1,3-dione (8.6 g.), xylene (157 m1.) and glacial acetic acid (78.5 ml.) was refluxed under a nitrogen atmosphere for 2 minutes. Then a solution of crude 2-(2-diethylaminoethyl)-6-(4,4-ethylenedioxypentyl)-2-tetrahydropyranol (23 g., as prepared in Example 7) in xylene (78.5 ml.) was added to the reaction mixture during 15 minutes. The mixture was then refluxed for another 15 minutes and then worked up by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo to give a crude mixture of 3-(4,4-ethy1enedioxypentyl) -6afi-methyl-2,3,5,6,6a,8-

hexahydrocyclopenta [f] 1 benzopyran-7(1H)-one,

hydroindene1,5(1H)-dione and 3-(4-oxopentyl)-6a 8-methyl-2,3,5,6,6a,8-hexahydrocyclopenta[f] [1]benzopyran-7(1H)-one.

This mixture was separated by chromatography on alumina. Elution with hexane afiorded 3-(4,4-ethylenedioxypentyl) 6a,8 methyl 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran-7(1H)-one, elution with hexaneether (92-1) afforded 3-(4-oxopentyl)-6a 8 methyl-2,3,5,6,6a, 8-hexahydrocyclopenta[f] [1]benzopyran-7(1H)-one and elution with chloroform afforded 4-(3-hydroxy-7-oxooctyl) 7a/3 methyl 2,3,5,6,7,7a hexahydroindene 1, (1H)-dione, an oil.

A mixture of pure 3-(4,4-ethylenedioxypentyD-Gaflmethyl 2,3,5,6,6a,8 hexahydrocyclopenta[f][l]benzopyran-7(1H)-one (2.86 g.), acetone (56 ml.) and 1 N sulfuric acid (5.6 ml.) was allowed to stand at room temperature for 18 hours. The workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo gave a crude mixture of 4-(3-hydroxy-7- oxooctyl) 7a,? methyl 2,3,5,6,7,7a hexahydroindene- 5,6,7,7a-hexahydroindene-1,5(1H)-dione (1.7 g.), benzene (50 ml.) and p-toluenesulfom'c acid (170 mg.) was refluxed for 2 hours. The workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo gave crude 3-(4-oxopentyl)-6ap-methyl-2,3,5,6, 6a,8 hexahydrocyclopenta[f][l]benzopyran 7(1H) one which was chromatographed on alumina (46.5 g.). Elution with hexane-benzene (9:1), (4:1), (1:1) and (1:2) afforded pure 3 (4-oxopentyl) '6afl-methyl2,3,5,6,6a,8- hexahydrocyclopenta [f] [l]benzopyran 7(1H)-one, thin layer chromatography, one spot).

EXAMPLE 28 A solution of 3-(4-oxopentyl)-6a,8-methyl-2,3,5,6,6a,8- hexahydrocyclopenta[f] [l]benzopyran 7(1H) one (1.36 g.) in tetrahydrofuran (60 ml.) was added at 0 C. within 15 minutes to a mixture of lithium aluminum hydride (262 mg.) in tetrahydrofuran (40 ml.), with stirring and under a nitrogen atmosphere. The reaction mixture was stirred for an additional 30 minutes at 0 C. and then worked up by careful addition of water, filtration and evaporation of the filtrate in vacuo at 38 C. yielding crude 3 (4 hydroxypentyl) 6a methyl 2,3,5,6,6a,8- hexahydrocyclopenta[f] [l]benzopyran 7 (1H) o1 (thin layer chromatography, one spot) was obtained.

EXAMPLE 29 A solution of 1 gram of 3-ethyl-6ap-methy1-2,3,5,6,6a, 8 hexahydrocyclopenta[f][l]benzopyran 7(1H) one in 20 milliliters of tetrahydrofuran was added over a 15- minute period to a stirred mixture of milligrams of lithium aluminum hydride in 25 milliliters of tetrahydrofuran maintained at 0 C. and under a nitrogen atmosphere. After stirring at 0 C. for an additional hour, a few drops of concentrated sodium hydroxide solution was added. The resulting solution was filtered and evaporated to give 0.982 gram of 3-ethyl-6aj3-methyl 2,3,5,6,6a,8- hexahydrocyclopenta [f l]benzopyran-7 1H)-o1 melting at 107-109 C.

Treatment of 235 milligrams of the product for 20 hours at room temperature with 0.28 gram of benzoyl chloride in 2 milliliters of pyridine as a solvent yielded the 7-benzoate ester.

Treatment of 200 milligrams of the product alcohol for 20 hours at 25 C. with 0.5 milliliter of acetic anhydride in 1 milliliter of pyridine yielded the 7-acetate.

EXAMPLE 30 Employing procedures similar to those described in Example 29 but substituting 3,6a 3-diethyl-2,3,5,6,6a,8- hexahydrocyclopenta[f] [l]benzopyran 7(1H) one for the 3 ethyl 6a,8 methyl 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran 7(1H) one, 3,6a 3 diethyl 2,3,5,6,6a,8 hexahydrocyclopenta[f][l]benzopyran 7 (1H)-o1 is produced.

EXAMPLE 31 In a manner similar to that described in Example 29, 3,6aB-dimethyl 2,3,5,6,6a,8 hexahydrocyclopenta[f] [1]benzopyran-7(lH)-one is reduced to its corresponding alcohol.

29 EXAMPLE 32 Employing procedures similar to those described in Example 29, 6aB methyl-3 propyl-2,3,5,6,6a,8 hexahydrocyclopenta[f] [1] benzopyran-7(1H)-one is reduced to 6a}? methyl-3 propyl 2,3,5,6,6a,8-hexahydrocyclopenta[f] [1] 'benzopyran-7(1H)-ol.

EXAMPLE 33 Employing procedures similar to those described in Example 29, except that 3-ethyl-6afi-methyl-1,2,3,5,6,6a,8,9- octahydro 7H naphtho[2,1-b]pyran 7-one is substituted for the 3-ethyl-6aB-methyl2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran-7(1H) one, there is produced 3 ethyl-Gap! methyl 1,2,3,5,6,6a,8,9-octahydro- 7H-naphtho[2,1-b] pyran-7-ol.

EXAMPLE 34 In a manner similar to that described in Example 29, 3,6215 diethyl 1,2,3,5,6,6a,8,9 octahydro-7H-naphtho- [2,1-b]-pyran-7-one is reduced to its corresponding alcohol.

EXAMPLE 35 A solution of a 1.37-gram portion of the optically active enol ether produced as described in Example 25 in 25 milliliters of tetrahydrofuran was added over a 15- minute period to a stirred solution of 137 milligrams of lithium aluminum hydride in 30 milliliters of tetrahydrofuran at C. and under a nitrogen atmosphere. After stirring for an additional 30 minutes at 0 C. and the addition of water to the reaction mixture, the mixture was worked up in the manner described in Example 29 to yield 1.39 grams of optically active 3-penty1-6afl-methyl 2,3,5,6,6a,8 hexahydrocyclopenta[f] [1]benzopyran- 7(1H)-ol.

EXAMPLE 36 A solution of crude 3-(4-hydroxypentyl-6afi-methyl- 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]-benzopyran 7 (1H)-o1 (1.52 g., obtained by the procedure of Example 28) in pyridine (15 ml.) was treated with acetic acid anhydride (7.5 ml.) at room temperature. After standing at room temperature for 20 hours the reaction mixture was treated with methanol (23 ml.) at 0 C. After standing for 30 minutes it was then extracted with benzene (3 times), the combined benzene extracts were washed with H O, in HCl, saturated NaHCO solution and again with H O. The benzene extract was then evaporated and the residue purified by chromatography on alumina (53.4 g.). Elution with hexane and hexane-ether (9:1) afforded pure 7fi-acetoxy-3-(4-acetoxypentyl)-6afimethyl 2,3,5,6,6a,8 hexahydro lH-cyclopenta[f][1] benzopyran (thin layer chromatography, one spot).

EXAMPLE 37 A mixture of 11,11-ethylenedioxy 1-dOdecene-3,7-diol (5.0 g.), acetone (100 ml.) and 1 N sulfuric acid (25 ml.) was stirred at room temperature for 6 hours. After the Workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo crude 11- oxo-1-dodecene-3,7-diol was obtained. This crude product was used for the next step.

A solution of crude 11-oxo-1-dodecene-3,7-diol (3.3 g.) in 1,2-dichlorethane (100 ml.) was treated with vigorous stirring with manganese dioxide (20 g.) at room temperature. After stirring for 1 hour, the manganese dioxide was filtered otf and washed with 1,2-dichlorethane. After evaporation of the combined 1,2-dichlorethane filtrates, crude 7-hydroxy-1-dodecene-3,1l-dione was obtained. This crude product was used for the next step.

A mixture of crude 7-hydroxy-1-dodecene-3,ll-dione (2.6 g.), 2-methyl-cyclopentane-1,3-dione (1.6 g.), toluene (35 ml.), pyridine (3.5 ml.) and hydroquinone (60 mg.) was refluxed with stirring for 2 /2 hours. After extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo crude 3-(4-oxophenyl)-6a,8- methyl 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran-7(1H)-one was obtained. This material was chromatographed on alumina g.). Fractions (90 ml. each) were taken as follows. 1-4=hexane-benzene (4:1), 5-8 =hexane benzene (2:1) and 9-12=hexane benzene (1:1). Fractions 3-12 afforded 3-(4-oxopentyl) 6aflmethyl 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran-7(1H)-one.

EXAMPLE 38 10.0 grams of 3,7-dihydroxy-1-nonene was dissolved in 300 milliliters of benzene and 20 milliliters of diethylamine (dist.). To this solution there was added, under vigorous stirring, at 25 C., 60.0 grams of activated manganese dioxide. The reaction mixture was then stirred at 25 C. for 15 hours and then at 45 C. for 5 hours. The manganese dioxide was then filtered off and the filtrate washed three times, each time, with 50 milliliters of benzene. It was then evaporated to dryness at 45 C. in vacuo yielding a crude product which by thin layer chromatography (thin layer chromatography system; Silica gel G plates, solvent benzene; diethylamine 9:1, detection 50 percent aqueous para-toluenesulfonic acid solution, C. Visibility of desired product l-diethyl-amino 7-hydroxy-nonan-3-one can be employed with I vapors) was shown to contain mainly 1-diethylamino-7 hydroxynonan-3-one plus traces of unreacted starting material 3,7-dihydroxy-1-nonene. This crude product was used without purification for the next step.

6.47 grams 'of 2-methylcyclopentane-1,3-dione, milliliters of xylene and 65 milliliters of glacial acetic acid was refluxed for 5 minutes. To the resulting solution there was added under refluxing and a nitrogen atmosphere during 15 minutes a solution of 13.25 grams of the above-prepared crude product containing l-diethylamino-7-hydroxy-nonan-3-one dissolved in 65 milliliters of xylene. The reaction mixture was then refluxed for 15 ,minutes. The resultant solution Was then cooled to 25 C. with an ice bath and then twice washed, each time with 100 milliliters of H 0, then twice, each time with 100 milliliters of saturated NaHCl solution and then again with 100 milliliters of H 0. The aqueous phases were twice extracted, each time with 200 milliliters of benzene. After evaporation of the combined xylene and benzene solutions at 55 C. in vacuo, light brownish crystals were obtained which were diluted with 50 milliliters of hexane, filtered off after 5 minutes, and twice washed, each time with 15 milliliters of hexane, yielding dl-3- ethyl-2,3,5,6,6a,8-hexahydro 6a/3 methylcycl0penta[f] 1]benzopyran-7(1H)-one (melting point 101-l02.5 C., beige crystals were obtained). Further quantities of this product were obtained from the mother'liquor by evaporation to dryness and column chromatography using aluminum oxide (40 grams, activity Grade III) and hexane as a solvent.

EXAMPLE 39 To a freshly prepared solution of methyl lithium (0.2 g.) in tetrahydrofuran (50 ml.), a solution of 3-ethyl-2, 3,5,6,6a,8-hexahydro 6afi methylcyclopenta[f][1]benzopyran-7(1H)-one (1.0 g.) in tetrahydrofuran (20 ml.) is added at 20 C. within 20 minutes with stirring and under a nitrogen atmosphere. After stirring for 1 hour at 50 C., the reaction mixture is poured onto ice (50 g.) ammonium chloride (5 g.). Extraction with ether (3 portions, 200 ml. each), washing with water (3 times, 50 ml. each), drying over sodium sulfate, filtration and evaporation gives 3-ethyl-7a,6aB-dimethyl-2,3,5,6,6a,8- hexahydrocyclopenta [f] [1]benzopyran-7 1H)-o1 which is further purified by preparative thin layer chromatogra phy on silica gel plates.

31 EXAMPLE 40 A solution of 6a,9a trans 3 ethyl-2,3,5,6,6a,8,9,9aoctahydro Gap methylcyclopenta [f] [l]benzopyran 7 (1H)-o1 (1.5 g.) in dimethylformamide (15 ml.) is slowly (30 minutes) added at 25 to a stirred mixture of chromic acid (0.3 g.), dimethylformamide (30 ml.) and concentrated sulfuric acid (1 drop). Stirring is continued for another 3 hours. After work-up (extraction of the reaction mixture with benzene, washing with water and evaporation of the benzene extracts in vacuo at 40) 6a, 9a-trans-3-ethyl-2,3,5,6,6a,8,9,9a octahydro-6a 3-methylcyclopenta[f] [1]benzopyran-7(1H)-one is obtained as an oil. After purification by column chromatography on aluminum oxide, this ketone is dissolved in tetrahydrofuran (25 ml.) and added (within 25 minutes) to a solution of lithium acetylide (prepared from 0.11 g. of lithium wire and acetylene in 50 ml. of liquid ammonia) at --35 C. with stirring. Stirring is then continued for 15 hours at the reflux temperature of the reaction mixture. After adding dry ammonium chloride (3 g.) and ether (50 ml.) to the reaction mixture, the ammonia was allowed to evaporate. After washing the ether phase with water (3 times), followed by filtration and evaporation in vacuo at 40, 6a,9a-trans-7u-ethinyl-3-ethyl-2,3,5,6,6a, 8,9,9a octahydro-6afi methylcyclopenta[f] [1]benzopyran-7(1H)-o1 is obtained as an oil. Purification is achieved by thick layer chromatography on silica gel plates.

. EXAMPLE 41 A mixture of 4.9 grams of 3-ethyl-6a,8-methyl-2,3,5,6, 6a,8-hexahydrocyclopenta[f][1]benzopyran 7(1H) 01 produced in a manner similar to that described in Example 29,.160 milliliters of methanol, 1.6 milliliters of 3 N sodium hydroxide, and 0.8 gram of 5 percent palladiumon-charcoal was stirred at room temperature in a nitrogen atmosphere. The hydrogen uptake stopped after 2 hours at which time 520 milliliters had been adsorbed. After addition of 0.3 milliliter of acetic acid, the catalyst was filtered off and the filtrate evaporated to dryness to yield 4.9 grams of product consisting predominantly of 6a,9a-trans-3-ethyl-6a/3-methyl-2,3,5,6,6a,8,9,9a-octahydrocyclopenta [f] 1 benzopyran-7 1H) -ol.

EXAMPLE 42 Employing apparatus and procedures similar to those described in Example 41, but substituting the product of Example 30 for that of Example 29, there is produced predominantly 6a,9a trans 3,6a 3-diethyl-2,3,5,6,6a,8,9, 9a-octahydrocyclopenta [f 1 1 ]-benzopyran-7(1H)-ol.

EXAMPLE 43 Employing apparatus and procedures similar to those described in Example 41 but substituting the product of Example 31 for that of Example 29, there is produced predominantly 6a,9a-trans-3,GaB-dimethyl-Z,3,5,6,6a,8,9, 9a-octahydrocyclopenta [f] l]-benzopyran-7 1H)-o1.

EXAMPLE 44 EXAMPLE 46 Employing apparatus and procedures similar to thosev described in Example 41 but substituting the product of .32 Example 34 for that of Example 29, there is produced predominantly 6a,10a-trans-3,6ap-diethyl 1,2,3,5,6,6a,8, 9,10,10a-decahydro-7H-naphtho- [2,1-b]pyran-7-ol.

EXAMPLE 47 The dienol of Example 35 was dissolved in 50 milliliters of toluene and then hydrogenated as described in Example 41, employing 378 milligrams of a 5 percent palladium-on-charcoal catalyst. After the uptake of 111 milliliters of hydrogen, there was obtained 1.39 grams of optically active 6a,9a-trans-3-pentyl-6a,3-methyl-2,3,5,6, 6a,8,9,9a octahydrocyclopenta[f][l] benzopyran 7 (1H)-o1.

EXAMPLE 48 A solution of 7,3-acetoxy-3-(4-acetoxypentyl)-6a 8 methyl 2,3,5,6,6a,8 hexahydro-lH-cyclopenta[f][1] benzpyran (1.31 g.; chromatographed) in toluene (50 ml.) was hydrogenated under normal conditions using 5 percent palladium-on-charcoal catalyst (262 mg). The uptake (88 ml.) of hydrogen stopped after 5 hours. The rworkup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and Water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo gave crude 6a,9a trans-7fl-acetoxy-3-(4-acetoxypentyl)-6aB-methyl- 2,3,5,6,6a,8,9,9a octahydro 1H-cyclopenta[r][1]benzopyran as an oil.

EXAMPLE 49 A solution of 11,11-ethylenedioxy-7-hydroxy-1-dodecen-3-one (6.7 g.; prepared as described in Example 7) in 25 ml. of toluene was treated with 2-methyl-l,3- cyclopentadione (3.50 g.), pyridine (2.7 ml.), and bydroquinone (140 mg), and the resulting mixture refiuxed for 8 hours using Dean-Stark apparatus.

At the end of the reflux period, the reaction mixture was chilled, the 2-methyl-1,3-cyclopentadione removed by filtration, and the filtrate concentrated in vacuo (water aspirator, 40). The crude product 3-[4,4-(etl1ylenedioxy) pentyl] 2,3,5,6,6a,8 hexahydro-6afi-methylcyclopenta [f][l]benzopyran-7(1H)-one (8.15 g.) was chromatographed on 82 g. of neutral alumina Grade III and the column eluted with hexane-10% ether. The eluted fractions 210 contained the desired product which was recrystallized once from isopropyl ether-hexane giving almost colorless crystals of 3-[4,4-(ethy1enedioxy)pentyl]- 2,3,5,6,6a,8 hexahydro 6a 3-methyl-cyclopenta[f][1] benzopyran-7(1H)-one, a sample of which upon being recrystallized from hexane-ether melted at 69-72.

EXAMPLE 50 To lithium aluminum hydride (0.38 g.) in tetrahydrofuran (90 ml.) at 0", a solution of the 3-[4,4-(ethylenedioxy)pentyl] 2,3,5,6,6a,8 hexahydro-6ap-methylcyclopenta[f] [l]benzopyran-7(lH)-one (3.7 g.) in 75 ml. tetrahydrofuran was added over a period of 15 minutes.

Upon completion of the addition of 3-[4,4-(ethylenedioxy)pentyl]-2,3,5,6,6a,8-hexahydro 6a;3 methylcyclopenta[f] [1]benzopyran-7(1H)-one, the mixture was stirred at 0 for 1 hour. A small amount of water was then added to the reaction mixture. Concentration of the reaction mixture in vacuo gave a yellow liquid which crystallized upon standing. The product, 3-[4,4(ethylenedioxy)pentyl] 2,3,5,6,6a,8 hexahydro-6a 3 -methylcyclopenta[f][1]benzopyran-7 1H)-o1, was collected by filtration.

A sample of the product, after recrystallization four times from dilute methanol and once from ether-hexane, melted at 9l-93 EXAMPLE 51 3 [4,4 (ethylenedioxy)pentyl]-2,3,5,6,6a,8-hexahydro 6a,8 methylcyclopenta[f] [1]benzopyran-7(1H)-ol (10 g.) was dissolved in 250 ml. of toluene and hydrogenated in the presence of 1.7 g. of 5% palladium-on- 33 charcoal catalyst. During ca. 9 hour period 710 ml. of H were consumed. The hydrogenation was performed at room temperature.

At the end of the reaction period the catalyst was removed by filtration, and the solvent removed in vacuo. The crude product was chromatographed on 100 g. of neutral alumina Grade III, and the column eluted with hexane-ether (1:2) giving purified product, 6a,9a-trans-3- [4,4 (ethylenedioxy)pentyl] 2,3,5,6,6a,8,9,9a-octahydro-6aB-methylcyclopenta[f] 1]benzopyran-7,( 1H -01.

EXAMPLE 52 A mixture of 465 milligrams of S-methyI-GaB-methyl- 2,3,5,6,6a,8 hexahydrocyclopenta[f][1]benzopyran 7 (1H)-one, as produced in a manner similar to that described in Example 8, 20 milliliters of toluene, and 150 milligrams of 5 percent palladium-on-charcoal was hydrogenated under ambient conditions. The hydrogen uptake ceased after one hour, after which time 50 milliliters had been adsorbed. After filtering the reaction mixture and evaporation of the filtrate, there was obtained the product monoenol ether as an oil containing predominantly 6a,9a cis 3-ethyl-6a 3-methyl-2,3,5,6,6a,8,9,9a octahydrocyclopenta [f] [11benzopyran-7 1H) -one.

EXAMPLE 53 Employing apparatus and procedures similar to those described in Example 52 but substituting the product of Example 19 for that of Example 8, there is produced predominantly 6a,9a, cis-3,6aB-diethyl-2,3,5,6,6a,8,9,9aoctahydrocyclopenta[f] [1]benzopyran-7 1H) -one.

EXAMPLE 54 Employing apparatus and procedures similar to those described in Example 52 but substituting the product of Example 22 for that of Example 8, there is produced predominantly 6a,9a-cis-3,6aB-dimethyl-2,3,5,6,6a,8,9,9aoctahydrocyclopenta [f] l benzopyran-7 1H -one.

EXAMPLE 5 5 Employing apparatus and procedures similar to those described in Example 47 but substituting the product of Example 23 for that of Example 7, there is produced predominantly 6a,9a-cis-6aB-methyl 3-propyl-2,3,5,6,6a, 8,9,9a octahydrocyclopenta[f] [1] benzopyran-7(1H)- one.

EXAMPLE 56 Employing apparatus and procedures similar to those described in Example 52 but substituting the product of Example 20 for that of Example 8, there is produced predominantly 6a,10a-cis-3-ethyl-6afi-methyl-1.2,3,5,6,6a, 8,9,10,10a-decahydro-7H-naphtho-[2,1-b]pyran-7-one.

EXAMPLE 57 Employing apparatus and procedures similar to those described in Example 52 but substituting the product of Example 21 for that of Example 8, there is produced predominantly 6a,10a-cis-3,6aB-diethyl 1,2,3,5,6,6a,8,9, l0,la-decahydro-7H-naphtho[2,l-b]-pyran-7-one.

EXAMPLE 8 A solution of the 4.9 grams of hydrogenation product obtaining in Example 41 in 100 milliliters of acetone and milliliters of l N sulfuric acid was held at 25 C. for minutes. After extraction of the reaction mixture with ether, washing with water and sodium bicarbonate solution, drying over sodium sulfate, filtration and evaporation, there was obtained 5.1 grams of crude 6a,9a-trans- 3-ethyl 6afi methylperhydrocyclopenta[f] [1]benzopyran-4a,7-diol. This product on crystallization from an ether-hexane mixture at 0 C. yielded 3.5 grams, melting point 1131l6 C. A second crop weighing 0.4 gram,.

melting point 114-117 C., was obtained from the mother liquor. The melting point was increased from 12l-122.5 C. after several additional recrystallizations.

34 By employing similar procedures but substituting methanol or acetic acid for the water, there are obtained the corresponding 4a-methoxyand 4a-acetoxy-derivatives, respectively.

EXAMPLE 59 Employing apparatus and procedures similar to those described in Example 58 but substituting the product of Example 42 for that of Example 41, there is produced predominantly 6a,9a trans 3,6a13-diethylperhydrocyclopenta [f] l benzopyran-4a,7-diol.

EXAMPLE 60 Employing apparatus and procedures similar to those described in Example 58 but substituting the product of Example 43 for that of Example 41, there is produced predominantly 6a,9a-trans-3,6afi dimethylperhydrocyclopenta [f] l benzopyran-4a,7-diol.

EXAMPLE 61 Employing apparatus and procedures similar to those described in Example 58 but substituting the product of Example 44 for that of Example 41, there is produced predominantly 6a,9a-trans-6afi methyl-3-propylperhydrocyclopenta [f] l]benzopyran-4a,7-diol.

EXAMPLE 62 Employing apparatus and procedures similar to those described in Example 58 but substituting the product of Example 45 for that of Example 41, there is produced predominantly 6a,l0a-trans-3-ethyl-6a,l3 methylperhydronaphtho [2,l-b] pyran-4a,7-diol.

EXAMPLE 63 Employing apparatus and procedures similar to those described in Example 58 but substituting the product of Example 46 for that of Example 41, there is produced predominantly 6a,l0a-trans-3,6a}8 diethylperhydronaphtho[2,1-b]pyran-4a,7-diol.

EXAMPLE 64 A 1.25-gram portion of the crude hydrogenation product obtained as described in Example 47 was dissolved in 25 milliliters of acetone and treated with 1 N sulfuric acid as described in Example 58. After standing at 25 C. for 45 minutes and workup of the reaction mixture, there was obtained 1.20 grams of optically active 6a,9atrans-3-pentyl-6afl-methylperhydrocyclopenta[f] [l] benzopyran-4a,7-diol as an oil.

EXAMPLE 65 A solution of 6-[4-(tbutoxy)pentyl]-tetrahydropyran- 2-01 (5 g.) in tetrahydrofuran (50 ml.) was added within 30 minutes at 5 to a solution of vinyl magnesium chloride in tetrahydrofuran, prepared from magnesium (2.0 g.) and 4 g. of vinyl chloride, dissolved in tetrahydrofuran (50 ml.). After stirring overnight at room temperature, the reaction solution was treated with ammonium chloride-ice and then extracted with chloroform (3 times, each time ml.). The organic phase was washed with water, dried and evaporated in vacuo giving crude 3,7- dihydroxy-1-1-(t-butoxy)-dodec-1-ene.

Crude 3,7-dihydroxy-l1-(t-butoxy)-dodec-1-ene (5.8 g., prepared as described above) Was dissolved in benzene (200 ml.) and the reaction mixture was then stirred for 2 hours at 25 after addition of activated manganese dioxide (58 g.). Filtration and evaporation of the filtrate at 30 in vacuo afforded crude 7-hydroxy-11-(t-butoxy)- dodec-1-en-3-one.

EXAMPLE 66 A mixture of crude 6a,9a-trans-7 3-acetoxy 3 (4-acetoxypentyl 6afl methyl 2,3,5,6,6a,8,9,9a octahydrolH-cyclopentaLf] [IJ-benzopyran (1,3 g., obtained by the procedure of Example 48), acetone (30 ml.) and 1 N sulfuric acid (15 ml.) was allowed to stand for 1 hour at room temperature. The workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo afforded crude 6a,9a-trans 3 (4- acetoxypentyl) 7,8 acetoxy Gafl methylperhydrocyclopenta[f] [l]benzopyran-4a-ol, which was purified by chromatography on alumina (67.5 g.). Fractions (68 ml. each) were taken as follows: 1-3=hexane-ether (9:1), 4--6=hexane-ether (4:1), 79=hexane-ether (2:1) and 10- 12=hexane-ether (1:1). Thin layer chromatography analysis showed fractions 4-10 (1.02 g. after evaporation) to be pure 6a,9a-trans-3-(4-acetoxypentyl)-7B-acetoxy- 6afi-methylperhydrocyclopenta [f 1]benzopyran-4a-ol.

EXAMPLE 67 6a9a trans 3 [4,4 (ethylenedioxy)pentyl]-2,3,5,6, 6a,8,9,9a octahydro 6afl methylcyclopenta[f][1]- benzopyran-7(1H)-o1 (9.04 g., obtained and purified as described in Example 51) was dissolved in acetone (180 ml.) and to this solution 90 ml. of 1 N H SO was added. The reactionmixture was allowed to remain at room temperature for 4 hours before it was neutralized with sodium bicarbonate solution, diluted with ca. 180 ml. of water, and extracted three times, each time with 200 ml. of chloroform. The extract was washed three times with water, dried, and the solvent removed to afford a slightly pink-colored, viscous liquid.

This crude product was chromatographed on 240 g. neutral aluminum Grade III, and the column eluted with hexane-ether (1 :2 and 1:9) followed by chloroformether (1:1). Several of the eluted fractions contained the desired product, 6a,9a trans 3-[4,4-(ethylenedioxy)- pentyl] 6afl methylperhydrocyclopenta[f][1] benzopyran-4a,7,3-diol.

EXAMPLE -68 Crude 7 hydroxy 11 (t butoxy) dcdec 1 en- 3-one (4.6 g., obtained as described in Example 65) was dissolved in toluene (46 ml.) and to this solution there was added Z-methylcyclopentane-1,3-dione (3 g.) pyridine (4.6 ml.) and hydroquinone (100 mg.). The reaction mixture was then refluxed for 8 hours, using a Dean- Stark water trap. The Workup and chromatography purification was performed as described in Example 8 and afforded 3 [4 (t-butoxy)-pentyl]-6afl-methyl-2,3,5,6, 6a,8-hexahydrocyclopenta [f 1]-benzopyran-7( 1H -one.

In order to remove the protective t-butylether group, a 1 g. sample of the product obtained above was refluxed for 5 hours under a nitrogen atmosphere in tetrahydrofuran (50 ml.) containing ml. of 1 N hydrochloric acid. Workup by extraction with ether, washing with water and evaporation to dryness in vacuo at 60 yielded 3 (4 hydroxypentyl) 6a,8 methyl 2,3,5,6,6a, 8-hexahydrocyclopenta [f] 1 1 benzopyran-7 1H) -one.

A sample of the so-prepared 3-(4-hydroxypentyl)-6aflmethyl 2,3,5,6,-6a,8 hexahydrocyclopenta[f][1]benzopyran-7(lH)-one (0.5 g.) was dissolved in ether (10 ml.) and reduced by reaction with a solution of lithium aluminum hydride (0.1 g.) in ether (10 ml.) at 0 (1 hour stirring). After addition of 10 drops of water, the reaction mixture was filtered and the filtrate evaporated giving 3 (4 hydroxypentyl) 6a methyl 2,3,5,6,6a, 8-hexahydrocyclopenta [f] [1 Jbenzopyran-7 1H) -ol.

EXAMPLE 69 Employing apparatus and procedures similar to those described in Example 58 but substituting the ketone of Example 52 for the 7-01 of Example 41, there is produced predominantly 6a,9a cis 3 ethyl 4a hydroxy 6a 3- methylperhydrocyclopenta [f] 1 Jbenzopyran-7-one.

EXAMPLE 70 Employing apparatus and procedures similar to those described in Example 58 but substituting the ketone of tives, respectively.

Example 53 for the diol of Example 41, there is produced predominantly 6a,9a cis 3,6afi-diethyl-4a-hydroxyperhydrocyclopenta [f] [1]-benzopyran-7-one.

EXAMPLE 71 Employing apparatus and procedures similar to those described in Example 58 but substituting the ketone of Example 54 for the diol of Example 41, there is produced predominantly 6a,9a cis 3,6ap dimethyl 4a hydroxyperhydrocyclopenta [f] 1]benzopyran-7-one.

EXAMPLE 72 Employing apparatus and procedures similar to those described in Example 58 but substituting the ketone of Example 56 for the diol of Example 41, there is produced predominantly 6a,l0a,-cis-3-ethyl-4a-hydroxy-6aflmethylperhydronaphtho[2,1-b]pyran-7-one.

EXAMPLE 73 Employing apparatus and procedures similar to those described in Example 58 but substituting the ketone of Example 57 for the diol of Example 41, there is produced predominantly 6a,10a cis-3,6a,B-diethyl-4a-hydroxyperhydronaphtho[2,1-b]pyran-7-one.

EXAMPLE 74 A mixture of 117 milligrams of 3-ethyl-6a 8-methyl-2,3, 5,6,6a,8 hexahydrocyclopenta[f][1]benz0pyran-7 1H)- 01 produced in a manner similar to that described in Example 29, 10 milliliters of isopropanol, 5 milliliters of 1 N sulfuric acid, and 20 milligrams of 5 percent pallad1- um-on-charcoal was hydrogenated at standard temperature and pressure. Workup of the reaction product in the manner described in Example 58,followed by crystallization from an ether-hexane mixture, gave 64 milligrams of 6a,9a trans 3 ethyl-6afi-methylperhydrocyclopenta- [f] [1]benzopyran-4a,7-diol, melting point l08112 C.

By employing similar procedures, but substituting methanol or acetic acid for the water, there are obtained the corresponding 4a-methoxyand 4a-acetoxy-deriva- EXAMPLE 75 A solution of 255 milligrams of 6a,9a-trans-3-ethyl- 6a,8 methylperhydrocyclopenta[f] [1]benzopyran 4a,7- diol produced as described in Example 58 in 10 milliliters of dichloromethane was treated with a solution of 200 milligrams of chromic acid in 5 milliliters of 3 N sulfuric acid and stirred at room temperature for 18 hours. The resulting reaction mixture was worked up as described in Example 58 to yield a crude product which was purified by chromatography on silica gel. Recrystallization of the thus-recovered product from an ether-hexane mixture yielded a sample of 6a,9a-trans-3-ethyl-4a-hydroxy-6a;9- methylperhydrocyclopenta [f] [l]benzopyran 7-one melting at 120--121.5 C.

EXAMPLE 76 A solution of 6.88 grams of chromic acid in 3.45 milliliters of 6 N sulfuric acid was added over a 20-minute period of a stirred solution of 3.5 grams of 6a,9a-trans- 3-ethyl 6a,s methylperhydrocyclopenta[f] [1]benzopyran-4a,7-diol, produced as described in Example 58, in 143 milliliters of acetone at 25 C. After stirring the reaction mixture for an additional 2% hours and workup as described in Example 58, there was worked up 3.0 grams of 3a,7a trans 4 (3-oxopentyl)-7afl-methyl-perhydroindene-1,5-dione. A solution of this product in 172 milliliters of toluene was treated with 792 milligrams of ptoluenesulfonic acid and refluxed for 3 hours using a Dean-Stark water separator. Workup and purification as described in Example 58 yielded 2.68 grams of desA- androst-9-ene-5,17-dione, which on crystallization from an etherisopropyl ether mixture, melted at 101-1025 C.

37 EXAMPLE 77 The product of Example 64 was oxidized with a mixture of 2.04 grams of chromic acid, 45 milliliters of acetone, and 10.2 milliliters of 6 N sulfuric acid in the manner described in Example 76 to yield 900 milligrams of 4 (3' -ketooctyl) 7aft-methyl-3aB-perhydroindene-1,5- dione. This triketone was treated with 205 milligrams of para-toluenesulfonic acid in 50 milliliters of toluene as described in Example 69 to yield 790 milligrams of d- -19-butyl-desA-androst-9-ene-5, l7-dione. After purification by chromatographing on silica gel, the product had an optical rotation [a] =-{60.5 as determined from a 30 percent solution in chloroform.

EXAMPLE 78 To a solution of chromatographed 6a,9a-trans-3-(4- acetoxypentyl) 7B acetoxy 6aB-methylperhydrocyclopent[f] [1]benzopyran-4a-ol (1.0 g.) in acetone (30 ml.), a mixture of chromic acid (1.0 g.) in 6 N sulfuric acid (5.3 ml.) was added at 20 C. (ice-cooling) with stirring during minutes. After this addition, the mixture was stirred for another 2 hours at room temperature. The workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo afforded crude 3a,7a trans-4-(7-acetoxy-3-oxooctyl)-1;3-acetoxy- 7a/B-methyl-perhydroindan-S-one as an oil. This product was used for the next step.

A mixture of 3a,7a-trans-4-(7-acetoxy-4-oxooctyl)-1B- acetoxy 7aB-methyl-perhydroindan-S-one (crude oxidation product; 940 mg.), benzene (20 ml.) and p-toluenesulfonic acid (94 mg.) was refluxed for 3 hours. Workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo gave crude 17pacetoxy (3 acetoxybutyl)-19-nor-desA-androst-9- en-5-one (870 mg.) which was purified by chromatography on silica gel (87 g.). Fractions (87 ml. each) were taken as follows: 1-3 =hexane-ether (4: 1), 4-6=hexaneether (2:1), 79=hexane-ether (1:1), 10-12=hexaneether (1:2) and 1315 =hexane-ether (1:4). Thin layer chromatographic analysis showed fractions 9-13 (583 mg. after evaporation) to be almost pure 17/3-acetoxy-10-(3- acetoxybutyl)-19-nor-desA-androst-9-en-5-one.

EXAMPLE 79 A solution of chromatographed 17fi-acetoxy-10-(3- acetoxybutyl)-19-nor-desA-androst-9-en-5-one (535 mg.) in absolute ethanol (30 ml.) and triethylamine (0.15 ml.) was hydrogenated under normal conditions using 5 percent palladium-on-charcoal catalyst (55 mg.). The uptake (31 ml.) of hydrogen stopped after about 5 hours. Workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo gave 17,3-acetoxy- 10-(3-acetoxybutyl)-19-nor-desA-androstan-S-one as an oil (535 mg.). This crude product was used for the next step.

A mixture of crude 17 8-acetoxy-10-(3-acetoxybutyl)- 19-n0r-desA-androstan-5-one (535 mg.), ethanol (20 ml.) and 20 percent sodium hydroxide solution (2.0 ml.) was allowed to stand at room temperature for 20 hours. Workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo afforded crude 17,8 hydroxy-lO-(3-hydroxybutyl)l9-nor desA- androstan-S-one (373 mg.). This crude product was used for the next step.

To a solution of crude 17,8-hydroxy-10-(3-hydroxybutyl)-19-nor-desA-androstan-5-one (373 mg.) in acetone ml.) a mixture of chromic acid (634 mg.) in 6 N sulfuric acid (3.2 ml.) was added over a period of 10 minutes with stirring and ice-cooling (20 C.). After this addition the reaction mixture Was stirred for another hour at room temperature. Workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo gave crude 10-(3-oxobutyl)-19-nordesA-androstan-S,l7-dione (307 mg.). Thin layer chromatographic analysis showed two major spots plus three minor spots. The two major spots were separated by chromatography on silica gel (30 g.). Elution with benzene-ether (2:1) aiforded a by-product. Elution with benzene-ether (1:1) afforded the desired product 10-(3- oxobutyl) l9-nor-desA-androstan-5,17-dione.

EXAMPLE A mixture of 10-(3-oxobutyl)-19-nor-desA-androstan- 5,17-dione (chromatographed product; 96.7 mg.), toluene (4 ml.) and p-toluenesulfonic acid (9.7 mg.) was refluxed for 3 hours. Workup by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtration at 50 C. in vacuo gave crude 19-nor-androst-4-ene-3,17-dione. This material was purified by chromatography on silica gel (8.5 g.). Elution was benzene-ether (1:1) afforded l9-nor-androst- 4-ene-3,17-dione (67.2 mg.). Upon recrystallization from ether-hexane d,1-19-nor-androst-4-ene-3,l7 dione melted at 156.5-158 C.

To a stirred solution of l9-nor-androst-4-ene-3,17-dione (56.8 mg.; chromatographed product) in tetrahydrofuran (2.5 ml.), tri-tert.-butoxylithium aluminum hydride mg.) was added at 0 C. in one portion. After stirring for 30 minutes at 0 C., the reaction mixture was worked up by extraction with ether (3 times), washing of the combined extracts with sodium bicarbonate solution and water, drying over sodium sulfate, filtration, and evaporation of the filtrate at 50 C. in vacuo to give rac. 19-nortestosterone as an oil. This material was chromatographed on silica gel (5.7 g.). Elution with benzene-ether (1:1) and benzene-ether (1:2) afforded rac. 19-n0rtestosterone which upon recrystallization from ether-hexane yielded rac. 19-nortestosterone melting at 116.5- C.

EXAMPLE 81 31.05 g. of 6a,9a-trans-3-ethyl-6afi-methylperhydrocyclopenta[f][1]benzopyran-4a,7-diol was dissolved in 490 ml. of acetone. A solution of chromium trioxide (32.4 g.) in 162 ml. of 6 N sulfuric acid was then dissolved into the resultant solution with stirring at 20 C. (cooling with ice bath) during the course of 20 minutes. After stirring the reaction mixture for 2 hours at 20 C., 100 ml. of water was added. The reaction mixture was then extracted with 400 ml. of benzene and then twice, each time with 300 ml. of benzene. The benzene extracts were twice washed, each time with 200 ml. of water and the combined benzene extracts were then dried over sodium sulfate and evaporated to dryness at 45 C. in vacuo yielding 29.5 g. of 4-(3-ketopentyl)flap-methyl- 3aa-perhydroindene-1,5-dione as a yellow oil. This was dissolved in 295 ml. of benzene and treated with 2.95 g. of para-toluenesulfonic acid. This mixture was then refluxed for 3 hours, after which it was cooled to 20 C., washed twice, each time with 100 m1. of water, twice, each time with 100 ml. of saturated sodium bicarbonate solution, and twice again, each time with 100 ml. of water. The aqueous phases were twice re-extracted, each time with ml. of benzene; the combined benzene extracts were dried over sodium sulfate. After evaporation to dryness at 45 C., crude desA-androst-9-ene-5, 17-dione was obtained as a brown oil. This crude product was then purified by column chromatography with aluminum oxide (265 g., active Grade 111). The first three fractions were eluted with hexane-benzene (4:1) and contained predominantly desA-androst-9-ene-5,l7-

beige crystals precipitated. The crystals were filtered off after a few hours at room temperature and washed with an equal amount of hexane-isopropyl ether (2:1) yielding d,1-desA-androst-9-ene-5,17-dione as yellow crystals melting at 100.5-102.0 C.

EXAMPLE 82 Employing procedures similar to those described in Example 29 but substituting 3-methyl-6a18-ethyl-2,3,5,6,6a, S-hexahydrocyclopenta [f] [1]'benzopyran-7( 1H) -one for the 3-ethyl-6afi-methyl-2,3,5,6,6a,8-hexahydrocyclopenta [f] [1]benzopyran-7 1H) -one, there is produced B-methyl- 6aj3-ethyl-2,3,5,6,6a,8 hexahydrocyclopenta [f] [l]benzopyran-7(1H)-ol.

EXAMPLE 83 Employing apparatus and procedures similar to those described in Example 41 but substituting the product of Example 82 for that of Example 29, there is produced predominantly 6a, 9a-trans-3-methyl-6aB-ethyl-2,3,5,6,6a,8,9, 9a-octahydrocyclopenta [f 1]-benzopyran-7(1H)-ol.

EXAMPLE 84 Employing apparatus and procedures similar to those described in Example 41 but substituting the product of Example 39 for that of Example 29, there is produced predominantly 6a, 9a-trans-3-ethyl-6aB,7a-dimethyl-2,3,5,6, 6a,8,9,9a octahydrocyclopenta[f][1]benzopyran-7(1H)- 01..

EXAMPLE 85 Employing apparatus and procedures similar to those described in Example 58 but substituting the product of Example 40 for that of Example 41, there is produced predominantly 6a, 9a trans 3 ethyl 7a ethinyl 6aflmethylperhydrocyclopenta [f] [1]benzopyran 4a,7 diol.

EXAMPLE 86 Employing apparatus and procedures similar to those described in Example 5-8 but substituting the product of Example 83 for that of Example 41, there is produced predominantly 6a, 9a-trans-6afl-ethyl-3-methylperhydrocyc penta [f] l benzopyran-4a,7-diol.

EXAMPLE 87 Employing apparatus and procedures similar to those described in Example 58 but substituting the product'of Example 84 for that of Example 41, there is produced predominantly 6a, 9a trans 6a)8,7a dimethyl 3 ethylperhydrocyclopenta [f] [1]benzopyran 4a,7 diol.

EXAMPLE 88 Employing apparatus and procedures similar to those described in Example 76 but substituting the product of Example 59 forthat of Example 58, there is prepared 3a, 7a trans 4 (3 oxopentyl) 7afi ethylperhydroindene 1,5 dione which is then converted to 18-nor-13,B- ethyl-desA-androst-9-ene-5,17-dione.

EXAMPLE 89 Employing apparatus and procedures similar to those described in Example 76 but substituting the product of Example 60 for that of Example 58, there is prepared 3a, 7a trans 4 (3 oxohexyl)-7afl-methylperhydorindeneindene-1,5-dione which is then converted to 19-nor-desA- androst-9-ene-5, 17-dione.

EXAMPLE 90 Employing apparatus and procedures similar to those described in Example 76 but substituting the product of 40 Example 61 for that of Example 58, there is prepared 3a, 7a-trans 4 (3' oxohexyl)-7a 3-methylperhydrorindene- 1,5-dione which is then converted to 19-nor-10-ethyldesA-androst-9-ene-5,17-dione.

EXAMPLE 91" Employing apparatus and procedures similar to those describedin Example 76 but substituting the product of Example 62 for that of Example 58, there is prepared 4a, 8a trans 5 (3' oxopentyl) 8afi methylperhydronaphthalene 1,6 dione which is then converted to desA- D-hom o-9-ene-5-,l7-dione.

EXAMPLE 92 Employing apparatus and procedures similar to those described in Example 76 but substituting the product of Example 63 for that of Example 58, there is prepared 4a,8a trans 5 (3' oxopentyl) 7afl ethylperhydronaphthalene 1, 6 dione which is then converted to 18-nor-13 S-ethyl-desA-D-homoandrost-9-ene-5,17-dione.

EXAMPLE 93 Employing apparatus and procedures similar to those described in Example 76 but submitting the product of Example 86 for that of Example 58, there is prepared 3a,7a trans 4 (3' oxobutyl) 7a,8 ethylperhydroindene 1,5 dione which is then converted to 18 nor 19-nor-13/8-ethyl-desA-androst-9-ene-5,17-dione.

EXAMPLE 94 Employing apparatus and procedures similar to those described in Example 76 but substituting the product of Example 87 for that of Example 58, there is prepared 3a, 7a trans 1,8 hydroxy 4 (3' oxopentyl) 1,7afi dimethylperhydroindene-5-one which is then convetered to l7 8-hydroxy-17a-methyl-desA-androst-9-ene-5-one.

EXAMPLE 95 3 -(4 oxopentyl 2,3,5,6,6a,8 hexahydro-6a 3-methylcyclopenta-[f][l]benzopyran-7(lH)-one (12 g.) is dissolved in 300 ml. of toluene and hydrogenated in the presence of 2.0 g. of 5% palladium-on-charcoal catalyst. During ca. 9 hour period 850 ml. of H is consumed. The hydrogenation is performed at room temperature.

At the end of the reaction period the catalyst is removed by filtration, and the solvent removed in vacuo. The crude product is chromatographed on g. of neutral alumina Grade III, and the column eluted with hexane-ether (1:2) giving a purified 6a, 9a-cis-3-(4-oxopentyl) 2,3,5,6,6a,8,9,9a octahydro 6afi methylcyclopenta [f] l benzopyran-7 1H -one.

EXAMPLE 96 A solution of 6a,9acis-3-(4-oxopentyl)-6a/3-methyl-2,- 3,5,6,6a,8,9,9a octahydrocyclopenta [f] [1]benzopyran-7- (lH)-one (680 mg.) in tetrahydrofuran (30 ml.) is added at 0 C. within 15 minutes to a mixture of lithium aluminum hydride (131 mg.) in tetrahydrofuran (20 ml.), with stirring and under a nitrogen atmosphere. The reaction mixture is then stirred for an additional 30 minutes at 0 C. and then worked up by careful addition of water filtration and evaporation of the filtrate in vacuo at 38 C. yielding crude 6a,9a-cis-3(4-hydroxypentyl)-6a/8-methyl- 2,3,5,6,6a,8,9,9a octahydrocyclopental [f] [1]benzopyran- 7-( 1H)-ol.

EXAMPLE 97 A solution of crude 6a,9a-cis-3-(4-hydroxypentyl)-6a- 9- methyl-2,3,5,6,6a,8,9,9a octahydrocyclopenta [f] [1]-benzopyran-7(1H)-ol (760 mg., obtained by the procedure of Example 96) in pyridine (7.5 ml.) is treated with acetic acid anhydride (3.75 ml.) at room temperature. After standing at room temperature for 20 hours the reaction mixture is treated with methanol (12 ml.) at 0 C. After standing for 30 minutes it is then extracted with benzene (3 times), the combined benzene extracts are washed with H O, in HCl, saturated NaHCO solution and again 

